Ion Channel Diseases

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ION CHANNELS, TRANSMITTERS, RECEPTORS & DISEASE

Channels & disorders
Anions
ATPase
Calcium
Cation
Chloride
Concepts
Cyclic nucleotide-gated
Gap junctions
Long QT Syndromes
Magnesium
Mitochondrial solute carriers
Na⁺, K⁺, Cl^- Co-transporters
Piezo
Potassium
HCN
KCN
K⁺/H⁺ ATPase
Proton-gated
Sodium
Na⁺/H⁺ exchangers
Non-voltage-gated
Voltage-gated
Toxins
Transient receptor potential

Channel binding proteins

Transmitters/Receptors
Acetylcholine
ATP
Capsaicin
Catecholamines
Dopamine
Glutamine
Glycine
Purines

Diagrams

CHANNEL TYPES: General ⁹

Extracellular ligand-gated channels: Nicotinoid
- 5 Homologous polypeptide subunits
- Subunits have 4 membrane spanning regions
- Ligands: Neurotransmitters
- Specific receptors
  - Nicotinic AChR
  - GABA_A & GABA_C
  - Glycine
  - 5-HT3
  - Glutamate activated anionic channels
Intracellular ligand-gated channels
- Ligands: cAMP, cGMP, Ca⁺⁺, G-proteins, Phosphorylation
Voltage-gated channels
- 4 domains
  - Na⁺ & Ca⁺ channels: In single polypeptide chain
  - K⁺ channel: Tetramer of 4 similar subunits
- Each domain has 6 membrane spanning regions
- S4 sequence
  - Contains + charged amino acids (lysine and/or arginine)
  - "Senses" voltage across membrane: Regulates pore opening
- Selective channel pore (Bacterial K⁺ channel model)
  - Dimensions: 12 Å long; 3 Å wide
  - Lined by main chain oxygen atoms
- Ion selectivity: Na⁺, Ca⁺⁺ or K⁺
Inward rectifier
- P domain: "Selectivity filter"
- 2 Flanking transmembrane region
- Homo- or heterooligomers in membrane
- Ion selectivity: K⁺
Gap junction channels
- 6 polypeptide subunits
- Each subunit has 4 membrane spanning regions
ATP gated channels: 3 Homologous polypeptide subunits

Chloride channels: Principles ¹⁴

Anion channels: General
- Classification schemes
  - Localization: Plasma membrane vs. vesicular
  - Single-channel conductance
  - Mechanism of regulation
  - Molecular structure
- Function
  - Allow the passive diffusion of negatively charged ions along electrochemical gradient
  - May conduct other anions (e.g., I^- or NO₃^-) better than Cl^-
  - Often called Cl^- channels because Cl^- is the most abundant anion in organisms
  - May perform functions in plasma membrane or in membranes of intracellular organelles
  - Functions often related to transport of charge
  - Cl^- does not seem to play a role as intracellular messenger
- Cl^- channel gating may depend on
  - Transmembrane voltage: Voltage-gated channels
  - Cell swelling
  - Binding of signaling molecules: Ligand-gated anion channels of postsynaptic membranes
  - Ions [e.g., Anions, H⁺ (pH), or Ca⁺⁺]: Intracellular Cl^- concentration may regulate channel activity
  - Phosphorylation of intracellular residues by various protein kinases
  - Binding or hydrolysis of ATP
General function of Cl^- channels in tissues
- Muscle: Contributes to resting conductance; Stabilizes resting potential; Loss produces myotonia
- Smooth muscle: Opening of Cl^- channels leads to depolarization
Structural classes of Cl^- channels
- Extracellular ligand-gated Cl^- channels (ELG)
  - 4 transmembrane domains in each subunit
  - Receptors function as pentamers
  - Types
    - Post synaptic
    - GABA & Glycine receptors
- Cystic fibrosis transmembrane conductance regulator (CFTR)
  - Family: ATP-binding cassette (ABC) transporters
  - Transmembrane domains: 2 Sets of 6
  - Sets separated by a cytoplasmic region with nucleotide binding fold (NBF1) & regulatory R domain
  - Channel opening is controlled by
    - Intracellular ATP
    - Phosphorylation by cAMP- or cGMP-dependent kinases
- Voltage-gated chloride channels (CLC)
  - Membrane-associated part of CLC channels is composed of 17 α-helices
    - Helix A is not inserted into the membrane
    - Most of the helices are not perpendicular to the membrane, but severely tilted
    - Helices may not span the width of the bilayer
  - Carboxy terminus of eukaryotic CLC proteins has two CBS domains
    - Unspecified role in protein-protein interaction
  - CLC channels are dimers: Each monomer has one pore (double-barreled channels)
  - CLC-K proteins
    - Associate with the β-subunit barttin which spans the membrane twice
  - CLC channel types
    - CLCN-1
      - Skeletal muscle, Placenta
      - Voltage stabilization
      - Mutation disorders
        
        Myotonia
        
        Paramyotonia
    - CLCN-2
      - Expression
        
        Ubiquitous
        
        Astrocytes, fibrous (GFAP+): Surface of Cell bodies & Processes
      - Function: Cell volume regulation
      - Physiology: Activated by hyperpolarization, cell swelling & acidic pH
      - Disorders
        
        Susceptibility: Epilepsy, juvenile myoclonic, juvenile absence or generalized
        
        Leukoencephalopathy with Ataxia (LKPAT)
        Hyperaldosteronism, type II (HALD2)
    - CLCN-3
      - Brain, Kidney (Type B intercalated cells), Skeletal muscle, Lung, Retina
      - Intracellular
      - Endosomes & Synaptic vesicles
      - Knockout: Degeneration of hippocampus & retina
      - Disorders
        
        Neurodevelopmental disorder with Hypotonia & Brain abnormalities (NEDHYBA)
        Neurodevelopmental disorder with Seizures & Brain abnormalities (NEDSBA)
    - CLCN-4
      - Muscle, Brain, Heart, Kidney, Retina
      - Vesicular channel
      - Disorder: Intellectual disability & Epilepsy (Raynaud-Claes syndrome)
    - CLCN-5
      - Kidney (Type A intercalated cells)
      - Endosomal channel
      - Renal endocytosis
      - ? Cl^- reabsorption
      - Disorder: Impaired renal endocytosis & Kidney stones
    - CLCN-6
      - Ubiquitous
      - Intracellular
      - Cl^-/H⁺-exchanger
      - Location Late endosomes of nervous system
      - Disorder
        
        Neurodegeneration, Childhood-onset, Hypotonia, Respiratory insufficiency & Brain imaging abnormalities (CONRIBA)
      - CLCN6-null mice
        
        Reduced pain sensitivity
        
        Behavioral abnormalities
        
        Enlarged proximal axons with autofluorescent electron-dense material, containing lysosomal proteins
    - CLCN-7
      - Brain; Testes; Skeletal muscle; Kidney
      - Lysosomal
      - Mutations: Osteopetrosis 4 & Lysosomal storage
    - ClC-0: Torpedo electric organ Cl^- channel
    - ClC-K/barttin channels: Transepithelial transport in kidney & inner ear
      - CLC-K1 (CLCN-KA) : Kidney
        
        Transepithelial Cl^- transport
        Location: Thin ascending limb of Henle loop in renal inner medulla
        Plays role in urine concentration
      - CLC-K2 (CLCN-KB)
        
        Kidney
        
        ? Cl^- reabsorption
        
        Clinical
        
        Bartter syndrome types 3 & 4
        Gitelman-like syndrome
- Nucleotide sensitive chloride channel (CLNS1A) : Volume sensitive
- Chloride intracellular channels
  - General
    - Location: Nuclear or Plasma membrane
    - No membrane spanning domains
    - Found vacuolar organelles
    - Function: Electrolyte composition & Acidification of intravesicular spaces
  - CLIC1 : Nuclear
  - CLIC2 : Xq28
    - Tissues: Skeletal muscle; Fetal liver
    - Function: Regulation of ryanodine receptor intracellular Ca⁺⁺ release channels (RyR)
    - Disorder: Intellectual Disability (XLID) & Cardiac (Atrial fibrillation, Cardiomegaly), Somatic features & Seizures
  - CLIC3 : Plasma membrane; Interacts with Erk7
  - CLIC4 : Brain, Heart, Placenta, Skeletal muscle
    - Role: Development of vascular collaterals in skeletal muscle & brain
  - CLIC5 : Heart; Skeletal muscle
- Calcium activated: Mediate a calcium-activated chloride conductance
  - CLCA1 : Intestinal basal crypt epithelium & goblet cells
  - Lung-endothelial cell adhesion molecule-1 (Lu-ECAM-1)
  - CLCA2 : Lung & trachea
    - Inhibitors: DIDS, Dithiothreitol, Niflumic acid, Tamoxifen
  - CLCA3 : ? Does not function as a channel protein
- Also see
  - Anion transporters
  - Na⁺, K⁺, Cl^- Co-transporters

Chloride channels: Disorders

Myotonia congenita (CLC-1)
- Dominant (Thompsen)
- Recessive (Becker)
Myotonic Dystrophy (DM1; DM2): Expanded CUG or CCUG repeats
- Retained in nucleus
- Disrupt splicing of chloride channel (ClC-1) pre-mRNA
Epilepsy
- CLC-2
  - Absence epilepsy: Childhood & Juvenile
  - Myoclonic epilepsy, Juvenile
  - Epilepsy with grand mal seizures on awakening
- Gamma-aminobutyric acid (GABA) receptors
  ● GABA receptor, γ-2 subunit(GABRG2) ; Chromosome 5q31.1-q33.1; Dominant
  - Generalized epilepsy with febrile seizures plus, type 3
  - Childhood absence epilepsy
  - Febrile seizures
Renal tubular disorders (CLC-5 )
- Hypercalciuric nephrolithiasis
- X-linked recessive Nephrolithiasis
- Dent disease
Nephrogenic diabetes insipidus (Mouse): (CLC-KA )
Bartter's syndrome (CLC-KB )
Cystic fibrosis (Epithelial chloride channel )
Osteopetrosis, infantile, malignant : CLC-7
Angleman or Prader-Willi: GABA_AB₃ receptor subunit
SLC26A4: Transporter of chloride & iodide
- Non-syndromic deafness, congenital
- Pendred syndrome
Alcohol non-tolerant rat: GABA_α6 receptor subunit
Glioma
- Cl^- channels upregulated in glioma cells
- High grade (poorly differentiated) tumors also lose Na⁺ channels
Toxin: Chlorotoxin (Scorpion)

Sodium channels: Principles

Types: Voltage-gated; Non-voltage-gated; Exchangers
- Voltage-gated Na⁺ channels
  - Function
    - Generate current to overcome membrane capacitance & resistance
    - Generate (Upstroke) & Propagate self-regenerating action potential
  - Associated proteins
    - Ankyrin_G
    - Neurofascin
  - Cellular Localization
    - Clustered at axon initial segments, Node of Ranvier & Post-synaptic folds of NMJ
    - Ankyrin_G necessary for clustering
  - Tissues
    - CNS: SCN1A; SCN2A; SCN3A; SCN8A; SCN9A (Hypothalamus)
    - Muscle: SCN4A; SCN5A (Denervated or Immature)
    - PNS: SCN7A; SCN9A; SCN10A; SCN11A
    - Heart: SCN5A
  - Structure: Often αβ1β2 heterotrimer
  - α subunits
    - Structure: 4 repeated domains; Each with 6 membrane spanning subunits; Glycosylated
    - Function: Forms ion pore; May be sufficient for funtional Na⁺ channel
    - Voltage sensor on 4th transmembrane domain
    - Different subtypes: Specific tissue localization
      - SCN1A (α1; I) : Na_v1.1
        
        CNS
        
        High levels in brain
        Dendrites
        
        Axons: Initial segment; Nodes of Ranvier
        
        Inhibitory interneurons
        
        Blockers: Tetrodotoxin; Saxitoxin
        Diseases & Mutations: Dominant inheritance
        
        Epilepsy, generalized, with Febrile seizures plus, type 2 (GEFSP2)
        Epileptic encephalopathy, early infantile, 6 (Dravet syndrome; EIEE6)
        Febrile seizures, familial, 3A
        Migraine, familial hemiplegic, 3 (FHM3)
      - SCN2A (α2; II; SCN2A1; SCN2A2) ³²: Na_v1.2
        
        Locations
        
        Most abundant form in brain
        Co-expressed with Na_v1.6: Excitatory, glutamatergic neurons; Unmyelinated axons of excitatory granule cells
        Peripheral nerve: Initial segment; Node of Ranvier
        Retinal ganglion cell: Unmyelinated initial axon segment
        Inhibitory interneurons: Largely express Na_v1.1 instead of Na_v1.2
        
        Blockers: Tetrodotoxin; Saxitoxin
        Initiation & Propagation of action potentials in some neurons
        Diseases & Mutations
        
        Epileptic encephalopathy, early infantile, Dominant 11 (EIEE11)
        
        Episodic ataxia, late-onset
        Myoclonus
        
        Pain
        
        Epilepsy: Some with Otahara syndrome
        Channel activity: Increased
        
        Episodic ataxia & Seizures, Child onset
        Seizures, benign familial infantile, Dominant 3 (BFIS3)
        Autism spectrum disorders with Global developmental delay
        
        Channel activity: Reduced
        
        Type 2 diabetes: Neuropathy susceptibility
      - SCN3A (α3; III) : Na_v1.3
        
        Brain: High levels; Early development
        Blockers: Tetrodotoxin; Saxitoxin
        Downregulated by: NGF; GDNF
        Disorders
        
        Epilepsy, familial focal, with variable foci 4, Dominant (FFEVF4)
        Epileptic encephalopathy, early infantile 62, Dominant (EIEE62)
      - SCN4A (μ1) : Na_v1.4
        
        Muscle
        
        Mature
        Sarcolemma: High levels
        
        NMJ: Concentrated at base of folded post-synaptic membrane
        
        Blockers
        
        Tetrodotoxin
        
        μ-conotoxins: GIIIA, GIIIB, GIIIC
        
        Diseases
      - SCN5A : Na_v1.5
        
        Tissues
        
        Heart; Initial phase of upstroke on EKG
        Skeletal muscle: Denervated; Immature
        
        Actions & Functions
        
        Tetrodotoxin & Saxitoxin resistant
        Associated with Caveolin-3 in myocardium
        
        Diseases
        
        Long QT syndrome 3
        
        Progressive cardiac conduction defect (PCCD2; Lenegre-Lev disease)
        Congenital non-progressive heart block
        Sudden infant death : S1103Y mutation, especially homozygosity
        Sudden unexplained nocturnal death
        Idiopathic ventricular fibrillation (Brugada 1)
        CMD 1E
        Atrial fibrillation, familial 10 (ATFB10)
        Heart block, progressive, type IA (PFHB1A)
        Ventricular fibrillation, familial, 1
        Sick sinus syndrome 1
        Brugada syndrome 1
      - SCN7A : Na_v2.x
        
        Locations
        
        Schwann cells: Non-myelinating
        Heart; Uterus; Skeletal muscle (Fetal & Denervated)
      - SCN8A (PN4) : Na_v1.6
        
        Brain & Spinal cord
        Cellular locations
        
        Primary channel at
        
        Node of Ranvier: Mature
        
        Axon: Initial segments
        
        Also: Dendrites; Synapses
        
        Physiology
        
        Currents: Fast transient; Smaller persistent (Contribute to intrinsic burst activity)
        
        Upregulation: Might produce hyperexcitability
        
        Diseases
        
        Epileptic encephalopathy, early infantile, 13 (EIEE13)
        Seizures, benign familial infantile, 5 (BFIS5)
        Cognitive impairment ± Cerebellar ataxia, Dominant or de novo (CIAT)
        Ataxia, Recurrent + Diplopia
        Myoclonus, familial 2, Dominant (MYOCL2) : Myoclonus in arms
        Mouse models
        
        motor endplate disease (med)
        
        dmu
        Allodynia, Mechanical: Vincristine-induced ³³
      - SCN9A (PN1) : Na_v1.7
        
        Locations
        
        Unmyelinated axons: Pain
        Similar to rat PN1: Dorsal root ganglia; Neuroendocrine (Adrenal & Thyroid)
        
        Properties
        
        Tetrodotoxin (TTX) sensitive
        
        See: SCN9A
        
        Diseases
      - SCN10A (PN3; SNS) : Na_v1.8
        
        Locations
        
        Small sensory neurons in PNS
        
        Unmyelinated axons: Pain
        
        Properties
        
        Depolarized activation potential
        Kinetics: Slow inactivation; Rapid repriming
        Tetrodotoxin resistant
        Upregulated by: NGF; GDNF
        DRG neurons
        
        Commonly expressed
        
        Carries most of Na⁺ current in action potential depolarizing phase
        
        Clinical associations
        
        Familial episodic pain 2 (FEPS2)
        Pain sensitization
        
        Cold-induced pain: Pain induced when skin is cold
        
        Diabetes: Painful neuropathy
        Oxaliplatin neuropathy, Acute
        Null mice: Analgesia to noxious mechanical stimuli
        Pathologic pain mediation associated with HCN2
      - SCN11A (NaN) : Na_v1.9
        
        Locations
        
        PNS: Free nerve endings
        Spinal sensory neurons: Dorsal root & Trigeminal ganglia
        
        Properties
        
        Tetrodotoxin resistant
        Upregulated by: NGF; GDNF
        Channel openining (rapid) stimulated by BDNF via BDNF binding to TrkB receptor
        Activated by relatively negative membrane potentials
        Peripheral inflammatory pain hypersensitivity
        
        Clinical associations
        
        Pain sensitization
        
        Congenital loss of pain perception
        
        Episodic pain, familial
        Na_v1.9 knockout mice: Analgesic
      - Other: Na-G (Glia); hNa_v (Heart)
  - β subunits
    - General function: Regulate ion-conducting α-subunits
    - SCN1B (β1)
      - Binding to α-subunit by non-covalent linkage
      - Associates with different forms of α-subunit in brain, heart & skeletal muscle
      - Provides inactivation kinetics to Na⁺ channel
      - Diseases
        
        Generalized epilepsy with febrile seizures +
        
        Brugada syndrome 5
        
        Atrial fibrillation, familial, 13 (ATFB13)
        Epileptic encephalopathy, early infantile, 52 (EIEE52)
    - SCN2B (β2)
      - Binding to α-subunit by disulfide bond covalent linkage
      - 1 transmembrane domain
      - N-terminal similarity to contactin, a neural adhesion protein
      - CNS localization
      - Disease
        
        Atrial fibrillation, familial, 14 (ATFB14)
    - SCN3B
      - Location: Brain, especially hippocampus; Adrenal; Kidney
      - Function
        
        Hyperpolarizing shift in voltage-dependence of inactivation
        
        Modulates α subunit: Increases fraction of channels operating in fast-gating mode
        
        SCN3B inactivates channel opening more slowly than SCN1B
      - Diseases
        
        Brugada syndrome 7
        
        Atrial fibrillation 16
    - SCN4B
      - Alters channel properties of SCN2A
        
        Shifts the voltage dependence of activation in toward hyperpolarization
        
        No change in voltage dependence of inactivation
      - Clinical association: Long QT syndrome 10
- Non-voltage-gated Na⁺ channels: Amiloride sensitive
  - SCNN: Epithelial sodium channel
    - Functions
      - Control Na+ resorption
      - Role in taste perception
    - Heterotrimer: αβγ or δβγ
    - Structure: 2 transmembrane domains
    - Blockade: Amiloride
    - Subunits
      - SCNN1A (α) : Pseudohypoaldosteronism I
      - SCNN1B (β) : Pseudohypoaldosteronism (Liddle syndrome)
      - SCNN1D (δ)
      - SCNN1G (γ) : Pseudohypoaldosteronism (Liddle syndrome)
  - Degenerins: Epithelial Na⁺ channel family
    - Characteristics
      - Amiloride sensitive
      - Neuronal: Brain; Spinal cord
      - Function: Mechanosensory channels
      - Permeable to Na⁺, K⁺ & Li⁺
      - Mutations: Activate channels & cause neurodegeneration in C. elegans
    - Types: Acid -sensing (Proton gated) ion channels
- Sodium/Hydrogen exchangers
  - Function: Eliminate acids from intracellular space
  - Activation: Low intracellular pH
  - Inhibition: Amiloride
  - Types
    - SLC9A1 (NHE1; NAH1)
      - Ubiquitous expression
      - Functions: Regulation of intracellular pH & cell volume
      - Disorders
        
        SCAR19: Ataxia-deafness (Lichtenstein-Knorr syndrome )
        Mouse mutant
        
        Slow wave epilepsy (3 Hz); Ataxia
        Pathology: Cerebellum (Deep nuclei) & brainstem
    - SLC9A2 (NHE2; NAH2)
      - Location: Intestine; Kidney
      - Function: Na⁺ ion absorption into mitochondria
    - SLC9A3 (NHE3; NAH3) : Insensitive to amiloride
    - SLC9A4 (NHE4; NAH4) : Stomach
    - SLC9A5 (NHE5; NAH5) : Brain, Testis, Spleen, Skeletal muscle
    - SLC9A6 (NHE6)
      - Location: Brain & Skeletal muscle > Other tissues
      - Subcellular location
        
        Early recycling endosomal membranes
        
        Transiently associates with the plasma membrane
      - Function: ? Role in regulating lumen pH
      - Colocalizes with internalized transferrin & early endosomal antigen 1 (EEA1)
      - Disorder: Mental retardation-Epilepsy-Ataxia syndrome
    - SLC9A7 (NHE7)
      - 12 N-terminal alpha-helical hydrophobic membrane-spanning segments
      - Location: Occipital lobe; Skeletal muscle; Secretory tissues
      - Functions
        
        Amiloride-insensitive, benzamil-sensitive influx of Na⁺ or K⁺ for H⁺
        
        Cation homeostasis & function of the trans-Golgi network
    - SLC9A8 (NHE8) : Gastrointestinal
    - SLC9A9 (NHE9)
      - Involved in effusion of Golgi luminal H⁺ in exchange for cytosolic cations
      - Ion homeostasis: Contributes to maintainance of acidic pH of Golgi & post-Golgi compartments
      - Subcellular location: Late endosome membrane
      - Multi-pass membrane protein
      - Ubiquitously expressed: Highest in heart & skeletal muscle
      - Disease: Autism susceptibility 16
    - SLC9A10 (NHE10) : Sperm specific
    - SLC9A11 (NHE11)
- Other Na⁺ exchangers
  - SLC5A
    - Sodium-glucose transporters
      - SLC5A1 : Glucose/Galactose malabsorption
      - SLC5A2 : Renal
    - Sodium/myoinositol cotransporter (SLC5A3)
    - Na⁺/I^- symporter (SLC5A5) : Congenital hypothyroidism
    - Sodium-dependent multivitamin transporter (SLC5A6)
      - Transport in GI tract & blood-brain barrier: Biotin; Pantothenic acid; Lipoate
      - Disease: Neurodegeneration, infantile-onset, Biotin-responsive (NERIB)
  - SLC24
    - Sodium/Potassium/Calcium exchanger (SLC24A1)

Sodium channels: Disorders

Skeletal Muscle
- SCN4A, α-subunit
  - Hyperkalemic periodic paralysis
  - Hypokalemic periodic paralysis
  - Paramyotonia congenita
  - Myotonia Fluctuans
  - Myotonia Permanens
  - Acetzolamide-responsive myotonia
  - Malignant hyperthermia
  - Myasthenic syndrome
  - Sudden infant death (1.4%) ³⁰
- Monensin overdose: Rhabdomyolysis
- SCN8A (PN4)
  - Diseases: motor endplate disease (med) mouse; dmu mouse
Peripheral nerve
- Localization of voltage-gated Na⁺ channels
  - RI: Soma
  - RII: Axonal initial segment & Node of Ranvier
- Hereditary
  - SCN4A: Oxalipaltin neuropathy, Acute
  - SCN9A : Familial erythermalgia
- Immune
  - Anti-GM1 ganglioside antibodies
    - Multifocal Motor Neuropathy
    - Acute motor axonal neuropathy
  - ? Guillain-Barré & CIDP
- Nerve injury
  - Neuromas: Accumulation of Na⁺ channels on axons in neuromas
  - Nerve transection
    - Down regulation:SCN10A; SCN11A
    - Up regulation: SCN3A
      - Contributes to hyperexcitability (Allodynia; Hyperesthesia)
- Na⁺ channel toxins
Brain & Spinal Cord
- α subunit: SCN1A disorders
  - Febrile seizures, familial, 3A
  - Generalized epilepsy with febrile seizures plus, Type 2 (GEFSP2)
    - Mutations
      - Missense
      - Location: S4 & S5 transmembrane segments
      - Mutation action: Disrupts channel inactivation
    - Inheritance: Dominant
    - Clinical: Mild seizure disorder
  - Myoclonic Epilepsy of Infancy: Severe (SMEI; EEIE6)
    - Nosology: Dravet syndrome with Motor neuropathy
    - Genetics
      - Chromosome 2q24; Dominant
      - Most mutations
        
        De novo
        
        Truncating type
        
        Disease mechanism: ? Haploinsufficiency
  - Infantile spasms
  - Migraine, familial hemiplegic, 3
- α subunit: SCN2A1
  - Seizure disorders
    - Benign familial neonatal-infantile
    - Febrile & Afebrile
  - Seizure disorder in mice
    - Mutation action: Disrupts channel inactivation
- α subunit: SCN8A
- β subunit: SCN1B
  - Generalized epilepsy with febrile seizures + (GEFS+1)
    - Mutation action: Disrupts channel inactivation
  - Dravet syndrome
Cardiac - α subunit: SCN5A
- Long QT Syndrome (LQT3)
- Idiopathic ventricular fibrillation (IVF)
- Progressive cardiac conduction defect (PCCD2; Lenegre disease)
  - Clinical syndrome: Syncope; Right bundle branch block
  - Genetics
    - DelG5280
    - Other locus: Chromosome 19q13.3
- Non-progressive congenital heart block
- Also see: SCN5A
Epithelial, Nonvoltage-gated, α & β subunits
- SCNN1A & SCNN1B
- Pseudohypoaldosteronism (Liddle's syndrome; Hereditary hypertension)
Thyroid
- Na⁺/I^- symporter (SLC5A5) : Congenital hypothyroidism
Endocrine
- Sodium-glucose transporter 1 (SLC5A1) : Glucose/galactose malabsorption
Neoplasms: Voltage gated Na⁺ channels
- Present in small cell lung cancer cell lines
- Associated with invasion by prostate cancer cells in vitro.
Na⁺ channel Toxins ¹
- Guanidinium: Saxitoxin; Tetrodotoxin
- Polypeptide
  - Scorpion toxins (α & β )
  - Sea anemone toxins
  - Conotoxins (δ & μ )
- Lipophilic:
  - Brevetoxins (Red tide), Veratridine & Aconitine: Open Na⁺ channels
  - Batrachotoxin; Ciguatoxin; Grayanotoxin
- Drugs: Lidocaine; Phenytoin

Voltage-gated Ca⁺⁺ entry channels: Principles

Ca⁺⁺ channels
- Contain 4 or 5 distinct subunits
- α₁ subunit
  - Pore-forming
  - Determines main biophysical & pharmacologic properties
α₁ subunits
- Subtypes: Numerous; Different tissue & peptide specificity
  - High voltage-activated (HVA)
    - α_1S (CACNA1S; L-type; Ca_v1.1) : Skeletal muscle; L-type DHP receptor
    - α_1C (CACNA1C; L-type; Ca_v1.2) : Heart, Fibroblasts, Lung, Smooth muscle
    - α_1D (CACNA1D; L-type; Ca_v1.3) : Brain (Striatum; Substantia nigra), Cochlea; Pancreas, Neuroendocrine
    - α_1F (CACNA1F; L-type; Ca_v1.4) : Retina
    - α_1A (CACNA1A; P/Q type; Ca_v2.1) : Brain, Motor neurons (Presynaptic terminals), Kidney
    - α_1B (CACNA1B; N-type; Ca_v2.2) : CNS, PNS
    - α_1E (CACNA1E; R-type; Ca_v2.3) : Brain, Muscle (NMJ)
  - Low voltage-activated (LVA; Ca_v3)
    - α_1G (CACNA1G; T-type; Ca_v 3.1)) : Brain
    - α_1H (CACNA1H; T-type; Ca_v3.2) : Kidney; Liver; D hair mechanoceptors
    - α_1I (CACNA1I; T-type; Ca_v3.3) : Brain
- Location: Transmembrane
- Functions
  - Voltage sensor
  - Ca⁺⁺ selective pore: Conductance
- Structure: Consists of 4 internal repeated domains (I-IV)
  - Domain I: responsible for channel activation kinetics
  - Each domain contains 6 α-helical transmembrane regions (S1-S6)
  - S4: Positively charged; Forms part of the voltage sensor
  - 2 additional domains between S5 & S6: Form pore region of channel
  - Verapamil & nifedipine bind
    - Helix 5 & 6 regions of domain III
    - Sequence after helix 6 of domain 4
  - Non N-glycosylated
  - Size: 160-273kD
  - Lambert-Eaton myasthenic syndrome: IgG binds to domains II & IV of α_1A subunit
- Binding drugs: Dihydropyridines; Verapamil; Diltiazem
- Disorders
  - CACNA1C: Brugada syndrome 3
Other subunits: Modulate channel functions
- α₂δ (CACNA2D)
  - General: Post-translationally cleaved into
    - α-2 protein: Long, N-terminal, Extracellular
    - δ polypeptide: Shorter, Membrane-anchored
    - α-2 and &delta: proteins: Covalently linked by disulfide bonds
  - CACNA2D1
    - Cell location: Membrane spanning
    - Structure
      - α₂ & δ: Derived from same gene & Linked by disulfide bridges
      - Glycosylated extensively on extracellular domains
    - Size: 140-170kD
    - Function: Regulatory
      - Increases amplitude of Ca⁺⁺ currents
    - Binding drug: Gabapentin
    - Skeletal muscle, Heart, Brain, Ileum
  - CACNA2D2
    - Locations: Lung & Testis > Brain, Heart, Pancreas
    - Auxiliary subunit of high voltage-gated calcium channels
    - Gabapentin receptor
    - Diseases
      - Cerebellar atrophy with seizures & variable developmental delay (CASVDD)
      - ? Early infantile epileptic encephalopathy
      - 'entla' mouse
  - CACNA2D3
  - CACNA2D4
    - Associated with coexpressed CACNA1C & CACNB3
    - Expressed at high levels in heart & skeletal muscle
    - Mutations in Autosomal Recessive Cone Dystrophy
- β (CACNB)
  - Location: Intracellular; Cytoplasmic
  - Size: 52-78kD
  - Subtypes
    - β₁ (CACNB1) : Skeletal muscle, Brain, Heart, Spleen
    - β₂ (CACNB2) : Brain, Heart, Lung, aorta
    - β₃ (CACNB3) : Many tissues
    - β₄ (CACNB4) : Brain, Kidney
  - Subtypes associate with different α₁ subunits in membrane
    - β₁ associates with α_1S
    - β_1B associates with α_1B & α_1E
    - β₄ associates with α_1A
  - Functions: Regulatory
    - Has cAMP-dependent protein kinase phosphorylation sites
    - Modifies current, voltage dependence & activation & inactivation
  - Disorders
    - CACNB2: Brugada syndrome 4
- γ (CACNG)
  - Cell location: Membrane spanning; No cytoplasmic domain
  - Size: 32kD
  - Subtypes
    - CACNG1 (γ1) : Skeletal muscle, Neuronal, Lung
    - CACNG2 (γ2) : Neuronal
    - CACNG3
    - CACNG4
    - CACNG5
    - CACNG6
    - CACNG7
    - CACNG8
  - Functions: Regulatory
    - Produce small increase in peak Ca⁺⁺ current & activation rate
    - Shift activation to more hyperpolarized membrane potentials
    - Auxiliary subunits AMPA-type glutamate receptor
      - CACNG types: 2,3,4,8
      - Regulate
        
        Early intracellular transport
        
        Synaptic targeting & anchoring
        
        Ion channel functions
  - Disorders
    - CACNG2: Mental retardation, Autosomal dominant 10
    - Mouse
Ca⁺⁺ channel classes (Voltage-gated): Related to α-1 subunit
- L-type (Long lasting) Ca⁺⁺ channel (Dihydropyridine receptors (DHPR))
  - Subunits: α_1C, α_1D, α_1F, or α_1S, α₂δ, β_3a
  - Physiology
    - Activation: Strong depolarization; Slow
    - Inactivation by depolarization: Little; Slow
    - Blockade
      - Sensitive to: Dihydropyridine (DHP) agonists and antagonists
      - Also blocked by phenylalkylamines (verapamil), benzothiazepines (diltiazem) & calciseptine
  - Localization
    - Skeletal muscle: α_1S
    - Brain (Neuronal soma & proximal dendrites): α_1D
    - Cardiac: α_1C; α_1D
    - Neuroendocrine: α_1D
    - Retina: α_1F
  - General function in muscle: Excitation-contraction coupling
    - Cav 1.1 (A1S): Skeletal muscle; Also acts as voltage sensor
    - Cav 1.2 (A1C): Heart & Smooth muscle
  - Diseases
- N-type Ca⁺⁺ channel
  - Subunits: α_1B, α₂δ, β_1b
  - Activation: Strong depolarization
  - Inactivation: Slow
  - Blockade: ω-conotoxin peptides
    - GVIA: Strong; Irreversible
    - MVIIA (Ziconotide; SNX-111): Analgesic activity
    - SO-3
  - DHP insensitive
  - Neuronal localization
    - Presynaptic
    - Nociceptive DRG neurons
  - Constituents: No γ subunit; Novel 100 kd subunit
  - Modulation ¹⁷
    - Enigma homolog (PKC binding protein) interacts with PKCe & N-type Ca⁺⁺ channels
    - Allows modulation of Ca⁺⁺ channel activity by PKCe
  - Functions
    - Transmitter release from presynaptic nerve terminals
    - From: Inhibitory γ-aminobutyric acid (GABA)ergic, Sympathetic noradrenergic & Dorsal root ganglion neurons
  - Diseases
- P-type Ca⁺⁺ channel
  - Subunits: α_1A, α₂δ, β_4a
  - Activation: Strong depolarization
  - Inactivation: Slow
  - Blockade
    - Funnel web spider venom (Agelenopsis aperta): w-agatoxin IVA
    - w-conotoxin MVIIC
  - Insensitive to DHP & w-conotoxin GVIA
  - Localization
    - Neuronal presynaptic
    - CNS: High concentration of α_1A subunit in
      - Cerebellum: Purkinje cells
      - Thalamus
    - Neuromuscular junctions
  - Function: Transmitter release
  - Diseases
- Q-type Ca⁺⁺ channel
  - Subunits: α_1A, α₂δ, β_4a
  - α_1A subunit is splice variant of α_1A in P-type channel
  - Activation: Strong depolarization
  - Inactivation: Slow
  - Blockade: ? more sensitive to w-conotoxin MVIIC than P-type
  - Location: Cerebellar granule cells; Hippocampal pyramidal neurons
  - Function: Transmitter release
- R-type Ca⁺⁺ channel
  - Subunits: α_1E (Ca_v2.3), α₂δ, β_1b
  - Activation: High threshold, strong depolarization
  - Inactivation: Voltage dependent; Rapid kinetics
  - Blockade: SNX-482 peptide from African tarantula, Hysterocrates gigas
  - Locations
    - Cerebellar granule neurons
    - Dendrites of hippocampal pyramidal neurons (Depolaarization)
    - Presynaptic terminals (Transmitter release)
  - Functions
    - Transmitter release
    - Insulin release: 2nd phase
  - Associated protein: EFHC1
    - Increases R-type Ca⁺⁺ channel currents
    - Mutations: Cause Juvenile myoclonic epilepsy
  - Action: Provide transient surge of Ca⁺⁺ influx
- T-type (Transient) Ca⁺⁺ channel ¹⁸
  - Subunits
    - May be formed by single α₁ subunit
    - α_1G (Ca_v 3.1)
      - Currents generate burst mode firing of action potentials in thalamocortical relay neurons
      - Generation of GABA-B receptor-mediated spike-and-wave discharges
      - Fastest recovery from inactivation
      - Disorder: Cerebellar ataxia, Dominant
    - α_1H (Ca_v 3.2)
      - Expression: Highest in kidney and liver; Also cardiac, neural, endocrine
      - Physiology
        
        Slowest recovery from inactivation
        Currents generate short burst firing
      - Inhibition mediated by G protein β-2 , γ-2 subunits
      - Neural
        
        D hair mechanoceptors
        Sympathetic ganglion neurons
        
        Nociceptive dorsal horn neurons: Regulate
        
        Spontaneous synaptic release of glutamate in superficial spinal laminae I-II
        
        Excitatory neurotransmission
      - Skeletal muscle: Embryonic; Associated with myoblast fusion
      - Disorders
        
        Childhood Absence Epilepsy in Northern China
        
        ALS
        
        Amyoplasia & Arthrogryposis
        
        Hyperaldosteronism, familial, type IV, Dominant
    - α_1I (Ca_v 3.3)
      - Brain specific
      - Functions
        
        LVA currents: Activate & inactivate much more slowly than typical T-type channels
        
        Currents contribute to sustained electrical activities in neurons
        Regulates
        
        Neuronal excitability
        
        Rhythmic activity of neuronal circuits
      - Disorder: Neurodevelopmental Disorder + variable Intellectual disability & Speech impairment ± Seizures (NEDISS)
  - Localization
    - Brain: All regions
    - Near Soma & on Dendrites
  - Activation
    - By depolarization near resting potential
    - Low voltage activation (LVA) threshhold
    - Facilitated by strong depolarizing pulses
    - Ca⁺⁺ competes with protons for binding to channel selectivity filter
    - Channels close slowly on repolarization of the membrane: Generates SD tail current
    - Tiny & equivalent single-channel conductance of Ba⁺⁺ & Ca⁺⁺
    - Generates Low threshold calcium spikes (LTS) in brain
  - Inactivation
    - Rapid
    - Steady-state inactivation occurs over a similar voltage range as activation
    - Window current: Small range of voltages where T-type channels can open, but do not inactivate completely
    - Rapid deinactivation
  - Reactivation: Requires strong hyperpolarization
  - T-type current regulation by G-protein coupled receptors
  - Conductance: Low (~8pS)
  - Blockade
    - Nickel ions: Especially Ca_v 3.2
    - Mibefradil
    - Kurtoxin: Peptide from South African scorpion, Parabuthus transvaalicus
    - TTA-P2
    - Ethosuximide: Not at therapeutically relevant concentrations
    - Do not bind dihydropyridines
  - Tissue localization
    - Cardiac & vascular smooth muscle
    - Nervous system: Thalamus; Dendrites & Cell bodies
  - Function
    - Rhythmic action (Pacemaker) potentials in cardiac muscle & neurons
    - Burst firing (Rhythmic) mode of action potentials
    - Regulate intracellular Ca⁺⁺ concentrations
Physiology of Ca⁺⁺ channels
- Low threshhold: T-type
- High threshhold (Activated at membrane potentials nearer 0 than resting): L, N, P-type

Other Ca⁺⁺ channels

Ligand gated Ca⁺⁺ entry channels
- Ca⁺⁺ transporting ATPase
  - ATP2A1 : Fast twitch skeletal muscle; Sarcoplasmic or endoplasmic reticulum
  - ATP2A2 : Slow twitch; 2 isoforms
    - SERCA2a: Heart & Slow-twitch skeletal muscle
    - SERCA2b: Smooth muscle & Nonmuscle tissues
  - ATP2B1 : Plasma membrane
  - ATP2B2 : Plasma membrane
  - ATP2B4
- Disorders
Capacitive Ca⁺⁺ entry channels
Intracellular activation channels
- General features
  - Homotetrameric complexes
  - Structure: 6 putative transmembrane sequences (TMSs)
  - Putative channel lining region between TMSs 5 and 6
  - Covalently linked carbohydrate on extracytoplasmic loops of channel domains
- Ca⁺⁺ release channels: Ryanodine receptors (RYR)
  - Signalling system: Cyclic ADP-ribose (cADPR)
  - Second messangers: cADPR-Ca⁺⁺-Calmodulin
  - Stimuli: Ca⁺⁺; Caffeine; Ryanodine
  - Inhibitors: Ryanodine
  - Activated by activity of dihydropyridine-sensitive Ca⁺⁺ channels
  - Function: Signal amplifier
  - Types
    - RYR1
      - Location: Skeletal muscle
      - Function: Involved in excitation-contraction coupling
      - Disorders
        
        Malignant hyperthermia
        
        Central core disease
        
        Immune: Antibodies vs RYR
        
        Granulomatous myopathy
        
        Myasthenia gravis
    - RYR2 : Cardiac
      - Channel
        
        Structure: Tetramer comprised of
        
        4 RYR2 polypeptides
        4 FK506-binding proteins (FKBP1A)
        
        Location: Sarcoplasmic reticulum
        Function
        
        Major source of Ca⁺⁺ needed for cardiac muscle excitation-contraction coupling
        Channel regulation by Protein kinase A (PKA)
        Phosphorylation of RYR2
        
        Dissociates FKBP1A from RYR2
        
        Regulates channel open probability
        
        RYR2 Macromolecular complex includes
        
        FKBP1A
        PKA
        Protein phosphatases PP1 & PP2A
        Anchoring protein, AKAP6
      - Disorders
        
        ARVD2
        Ventricular tachycardia, Catecholaminergic, Polymorphic 1 (CPVT1)
    - RYR3 : Brain & Muscle
      - Disorder: Rod myopathy
- Inositol-1,4,5-triphosphate (IP3) receptors
  - Location: Brain cell endoplasmic reticular (ER) membranes
  - Activated by increase intracellular levels of IP3
  - Structurally similar to ryanodine receptors
  - Cause release of intracellular Ca⁺⁺ stores after stimulation of cell surface receptors
  - Function: Signal oscillation
Other intracellular Ca⁺⁺ channels ⁵
- Nicotinic acid adenine dinucleotide phosphate (NAADP) receptor
  - Signalling system: Cyclic ADP-ribose (cADPR)
  - Releases Ca⁺⁺ from a thapsigargin-insensitive store
  - Second messenger & Stimulus: Nanomolar NAADP
  - Inhibition: High NAADP
  - Function: Signal trigger
- Sphingolipid receptor (EDG1)
  - Signalling system: Sphingolipid pathways
  - Second messenger: ? Sphingosine-1-phosphate (S1P) or Sphingosyl-phosphorylcholine (SPC)

Ca⁺⁺ sensors

Type A: Expressed in photoreceptor cells; function
- Recoverin
- Visinin
- S-modulin
Type B: Expressed in neurons
- VILIP
- Neuronal calcium sensor-1 (NCS1) : Associated with secretory granules

Ca⁺⁺ channel disorders

L-type Ca⁺⁺ channel, voltage-gated; Skeletal muscle (CACNL1A3 α_1S) & other subunits
- CACNA1S (DHPR; CACNL1A3 α_1S subunit; Ca_v1.1)
- CACNA1C (Ca_v1.2)
  - Timothy syndrome (Cardiac arrhythmia, Cognitive impairment, Autism)
  - Long QT (LQT) syndrome with syndactyly
  - LQT8
  - Neurodevelopmental disorder + Hypotonia, Language delay & Skeletal defects ± Seizures
  - Brugada syndrome 3
- CACNA1D
  - Sinoatrial node dysfunction & Deafness (SANDD)
  - Primary aldosteronism, seizures & neurologic abnormalities (PASNA)
- CACNA1F (Ca⁺⁺ channel, voltage-gated; α_1F subunit; Ca_v1.4) : Retina specific subunit
  - X-linked congenital stationary night blindness: Incomplete form (CSNB2)
  - Aland Island eye disease
  - Cone-rod dystropy, X-linked, 3
- ? α2/δ subunit: Malignant hyperthermia
- Mouse models
  - Muscular dysgenesis mouse: Absent α_1S (CACNA1S) subunit
  - Deafness: CACNA1D deficiency
- Toxins: Skeletal & smooth muscle
  - Polypeptides: Mamba snake (Calciseptine )
  - Dihydropyridines: Nifedipine...; Diltiazem; Verapamil
- Self-biting & self-injurious behavior: Activation of CACNA1D containing L-type channels ((+/-)Bay K 8644)
N-type Ca⁺⁺ channel
- Toxins: Polypeptide
  - w-conotoxin SVIA
  - SNX-325 (Segestria spider toxin)
- ? Neuropathic pain (Ca_v3.1)
P-type Ca⁺⁺ channel, voltage-gated; Presynaptic terminal of motor axon
- Immune
  - Antibodies
  - Lambert-Eaton Myasthenic Syndrome (LEMS)
- w-agatoxins: Especially IVA & IVB
- CACNA1A (CACNL1A4; Ca_v2.1) α_1A subunit ¹
  - Episodic ataxia type-2
    - Truncating mutations in repeat domain III
    - Probably produce non-functioning channel
    - Haploinsufficiency & mild cerebellar pathology
  - Familial hemiplegic migraine
    - Missense mutations in transmembrane segments: Channel hyperactivity
  - Ataxia, Progressive: SCA 6
    - Trinucleotide repeat expansion in intracellular region near carboxy terminus
    - Missense mutation: G293R
  - Epilepsy ± Migraine: R1820stop mutation
  - Ataxia, Congenital
    - Congenital ataxia, Mental retardation, Dyskinesia, Recurrent Coma: IIe712Val; R1350Q
    - Early onset ataxia: Global delay; Nystagmus; Thr666Met (Also associated with hemiplegic migraine)
  - Early onset Developmental delay & Congenital ataxia ± Seizures
    - de novo CACNA1A missense (p.R1664Q): S4 transmembrane segments; Loss of function
  - Epileptic encephalopathy, early infantile, 42
  - Mouse mutations: Loss of both alleles ® prominent cerebellar degeneration
    - Tottering leaner
      - Recessive
      - Ataxia
      - Splicing mutation
      - Produces truncated protein
      - Physiology: Alteration in the whole-cell calcium current in Purkinje cells
    - Tottering
      - Recessive
      - Ataxia; Absence seizures (spike-wave)
      - Missense mutation in extracellular pore region of repeat domain II
      - Physiology at neuromuscular junctions
        
        Greater Run-down of evoked acetylcholine release at high-rate stimulation
        
        Greater Spontaneous acetylcholine release from presynaptic terminals
    - Rolling Nagoya
- CACNB4 β4 subunit
  - R482X: Juvenile myoclonic epilepsy ⁶
  - C104F: Generalized epilepsy & praxis-induced seizures; Episodic ataxia (EA5)
R-type Ca⁺⁺ channel, voltage-gated; α_1E subunit (CACNA1E)
- ? Hemiplegic migraine
- Mouse Ca_v2.3 α1 subunit loss: Reduced sensitivity to inflammatory pain
- R-channel antagonists in dorsal horn: Elicited analgesia in neuropathic pain models
T-type Ca⁺⁺ channel, voltage-gated
- Cerebellar ataxia, dominant (CACNA1G)
- Absence epilepsy (CACNA1H)
  - Childhood Absence Epilepsy in Northern China ¹⁹: Missense mutations of CACNA1H (Ca_v3.2)
  - Rat model: Greater current in reticular thalamic neurons
- Central pain: Antinociceptive mechanisms (Ca_v3.1)
- Possible drug effects: Ethosuximide; Valproate
Ca⁺⁺ release channels (Ryanodine receptors)
- Ryanodine receptor 1
  - Malignant hyperthermia
  - Central core disease
  - Granulomatous myopathy: Antibodies vs RYR
- Ryanodine receptor 2
  - Ventricular tachycardia, stress-induced polymorphic
  - Right ventricular dilated (ARVD) cardiomyopathy 2
Ca⁺⁺ transporting ATPase
- ATP2A1
  - Brody myopathy
- ATP2A2
  - Darier-White disease: Keratosis follicularis
- ATP2B2
  - Deafwaddler (dfw) mouse: Deafness; Vestibular imbalance
Mouse mutants: Other
- β₁ null mutant mouse
  - Lacks excitation-contraction coupling: Dies at birth
- Ca⁺⁺ channel, voltage dependent, β4 subunit (CACNB4)
  - Lethargic (lh) mouse: Seizures; Ataxia
- Ca⁺⁺ channel, voltage dependent, γ2 subunit (CACNG2)
  - Stargazer: Absence epilepsy; Head tossing; Ataxia
  - Waggler: Absence epilepsy; Head tossing; Ataxia
- CACNA2D2 : Ducky mouse; Ataxia & Slow wave seizures

Types
HCN
KCN
A; B; C; D;
E; F; G; H;
J; K; M; N;
Q; S; T; V
KCTD
H⁺/K⁺-ATPase
Plasmolipin
SUR

Principles & Types of K⁺ Channels

Structure ⁴
- K⁺ channel
  - Inner & Outer membrane face
    - Layers of aromatic amino acids: Tryptophan; Tyrosine
    - Form cuff around pore
    - Pull pore opening like springs
  - Selectivity filter
    - Narrow region near outer face of membrane
    - Contains glycine-tyrosine-glycine residues
    - Lined by carbonyl backbone of conserved amino acids
    - ? Carbonyl oxygens act as surrogate H₂O: Coordinate 2 dehydrated K⁺ ions sitting in line in channel
  - Ions travel through channel in single file
- Voltage gated K⁺ channels (Kv)
  - 6 Transmembrane (TM) regions (S1-S6)
  - 4 Subunits surround central pore (TM channel): S5 & S6 regions of each subunit
  - Selectivity filter (P region): Hydrophobic sequence between last 2 TM regions; Contains Gly-Tyr-Gly
  - Voltage sensing: Multiple positively charged amino acids in 4th TM region (S4)
- Inwardly rectifying K⁺ channels (Kir)
  - 2 Transmembrane regions (M1 & M2): Correspond to last 2 TM regions (S5 & S6) in Kv channels
  - 4 Subunits surround central pore (TM channel)
  - P region: Separates M1 & M2
  - Non-conducting at positive membrane potentials
  - Kir families & types
- K_Ca channels
  - 6 Transmembrane domains
  - Activated in response to Ca⁺⁺ influx via voltage channels
  - Reduce excitability after depolarization
  - Subtypes
    - BK_Ca (Maxi K)
      - Gated by: Both voltage & intracellular Ca⁺⁺
      - Link cell excitability with cell signaling and metabolism
    - IK
    - SK
K⁺ channel functions: Often voltage-sensitive
- Voltage gated K⁺ channels (Kv)
  - Role in determining membrane excitability & duration of the action potential
- Delayed rectifier K⁺ channels
  - Delayed activation; Slow inactivation
  - Allows efficient repolarization after action potential
  - Blockers: 4-aminopyridine; Dendrotoxins; Phencyclidine; Phalloidin; 9-aminoacridine;
    Margatoxin; Imperator toxin; Charybdotoxin
  - Structure: Tetramer of α-subunits ± β-subunit
- Inward rectifier K⁺ channels (Kir)
  - General properties
    - Inward-rectifying: Passes current (positive charge) more easily into, than out, of the cell
    - K⁺ channel: Greater tendancy to allow potassium to flow into cell rather than out
    - Voltage dependance: Regulated by concentration of extracellular potassium
    - Inward rectification mainly due to: Blockage of outward current by internal magnesium & polyamines
    - Can be blocked by external Ba⁺⁺
    - Subcellular location: Integral membrane protein
    - Activity of Kir channels: Dependent on interactions with phosphatidylinositol 4,5-bisphosphate (PIP2)
  - Functions
    - Maintain resting membrane potential near equilibrium potential for K⁺ ions
    - Contribute to cell excitability
    - Tissues: Excitable; Heart, Brain, Skeletal muscle
    - Non-conducting at positive membrane potentials
  - Typical Kir: Large family
    - Roles in excitability & resting conductance of muscle cells and neurons
    - Some ATP-sensitive or GTP-activated
    - Structure
      - 2 membrane-spanning domains in each subunit (M1 & M2)
        
        Correspond to last 2 TM regions (S5 & S6) in Kv channels
      - N-terminal domain: Intracellular
      - C-terminal domain: Intracellular
      - No voltage sensor in voltage-gated channels
      - Homologous to regions in voltage-gated K⁺ channel
        
        Transmembrane regions 5 (M1) & 6 (M2)
        P region
        
        Separates M1 & M2
        Pore helix
        Loop region: Major ion selectivity filter; Amino acid TVGYG core
      - Subunit clustering
        
        Homotetramers or Heterotetramers
        
        4 Subunits surround central pore (TM channel)
    - Currents
      - Large inward at potentials negative to K⁺ equilibrium potential
      - Small outward currents at more positive potentials
    - Blockers: LY97241; Gaboon viper venom; Sr⁺⁺; Ba⁺⁺; Cs⁺
    - Regulation: External K⁺; Internal Mg⁺⁺; Intracellular polyamines, ATP or G-proteins
  - ATP-sensitive K⁺ channels (Kir 6) ²⁵
    - General
      - Couple cellular energy metabolism to membrane electrical activity
      - Inhibitory effect: Intracellular ATP
        
        ATP acts from the cytoplasmic face of membrane
        
        ATP reduces K⁺ channel open probability
        \
        Decrease in ATP
        
        Opens channel
        
        Leads to cell hyperpolarization & decreased activity
        
        Facilitation: Nucleoside diphosphate
    - Components
      - K+ pore: Inwardly rectifying Kir6 subunits
        
        KCNJ8: Kir 6.1
        
        KCNJ11: Kir 6.2
      - Regulatory subunits: Sulphonylurea receptors (SURs)
        
        Members of the ATP-binding cassette (ABC) family
        
        SURs: SUR1 & SUR2
    - Properties
      - Inwardly rectifying; pH sensitive
      - Not voltage-dependent
    - Openers: Levcromakalim; Diazoxide; Aprikalim; Pinacilil
    - Blockers: Glibenclamide; Tolbutamide; Phentolamine: Ciclazindol; Lidocaine
    - Structure: Tetramer of 2-transmembrane subunits
    - Brain
      - Kir 6.2 subunits present in hypothalamus, basal forebrain cholinergic neurons & striatum: Protect against hypoxic insults
    - Functions
      - Couples membrane K⁺ conductance (membrane potential) of cell to metabolic state
      - Senses intracellular nucleotide concentrations
      - Role in many tissues: Response to metabolic changes such ashypoxia, ischaemia
      - Glucose concentration sensor in β-cells
        
        Underly insulin secretion due to increase in blood glucose concentration
      - Heart
        
        Protective function: Response to hypoxia or ischaemia
        
        Underlie responses to metabolic or catecholamine stress
      - Skeletal muscle
        
        Roles in fatigue & glucose uptake
  - Two pore channels (K_2P)
    - α-subunits: Consist of four transmembrane segments & two pore domains
    - Provide for baseline resting K⁺ currents
    - Roles
      - Set resting membrane potential
      - Contribute to: Modulation of action potential duration; Responsiveness to synaptic stimuli
      - Oxygen, pH & glucose sensing
      - Target of local & volatile anesthetics
  - Human ether-a-go-go (HERG; KCNH) : Atypical with 6 transmembrane domains
  - See: Specific channel types; Disorders
- Ca⁺⁺ sensitive K⁺ channels (K_Ca): Generate membrane potential oscillations; Afterhyperpolarization
  - General structure & function ¹⁵
    - 4 protein subunits
    - 6 transmembrane domains
    - Each subunit contributes one membrane-spanning segment (Helical structure) to the pore lining
    - External surface: Contains selective K⁺ filter; Formed by backbone carbonyls
    - Inner cavity: Accommodates a hydrated K⁺ ion
    - Cytoplasmic side of channel
      - Subunit helices form a bundle of RCK domains whch act as gate
      - RCK domains have fixed & flexible interaction domains
      - 2 Ca⁺⁺ ions bind to flexible RCK interaction domains & regulate gate
    - Depend on intracellular Ca⁺⁺ for opening
  - High conductance (BK; KCNMA1)
    - Gated by internal Ca⁺⁺ and membrane potential
    - Unit conductance: 100 to 220 picoSiemens (pS)
    - Openers: NS004; NS1619; DHS-1
    - Blockers: Iberiotoxin; (+)-tubocurarine; Charybdotoxin; Noxiustoxin; Penitrem-A; TEA
  - Intermediate conductance (IK; K_Ca3.1; KCNN4)
    - More sensitive to Ca⁺⁺ than BK channels
    - Gated only by internal Ca⁺⁺ ions
    - Unit conductance: 20 to 85 pS
    - Purkinje cells
      - Activation
        
        By local, activity-dependent Ca⁺⁺ influx at CNS nodes of Ranvier: Via T-type voltage-gated Ca⁺⁺ current
      - Opposes depolarizing block at nodes
      - Supports continuous axonal spike propagation in spontaneously firing cells
    - Endothelial cells
      - IK location
        
        Projections of endothelium through internal elastic lamina
        
        Contact area with smooth muscle cells
    - Acetylcholine (ACh)-induced vessel dilation in skeletal muscle arterioles
      - Mechanism: Endothelial hyperpolarization
      - Endothelium-derived hyperpolarizing factor (EDHF)-type dilation responses
    - Blockers: Cetiedil; Trifluoroperazine; Haloperidol
  - Small conductance (SK; K_Ca2.3; KCNN3): Minimal voltage-gating (KCNN; ISK-family)
    - More sensitive to Ca⁺⁺ than BK channels
    - Gated only by internal Ca⁺⁺ ions
    - Voltage independent
    - Unit conductance: 2 to 20 pS
    - Blockers: Apamin ; Leiurotoxin 1 ; (+)-tubocurarine; UCL-1684
    - Endothelial cells
      - Locations: Surface; Caveolae with connexins Cx 37, Cx40 & Cx43
      - Function: Endothelial hyperpolarization
- Na⁺ activated K⁺ channels
  - Voltage-insensitive
  - Blockers: Mg⁺⁺; Ba⁺⁺
- Cell volume sensitive K⁺ channels
  - Activated by increased cell volume
  - Blockers: Quinidine; Lidocaine; Cetiedil
- Type A K⁺ channels: Rapid activation & inactivation
  - Blockers: 4-aminopyridine; Quinidine; Mast cell degranulating peptide; Phencyclidine; Dendrotoxins
  - ? Regulation of fast repolarizing phase of action potentials: Delay spiking
  - Structure: Tetramer of α-subunits + intracellular β-subunits
  - β-subunits may confer rapid inactivation
- Receptor-coupled K⁺ channels
  - Muscarinic-inactivated
    - Slow activation; Non-inactivating; Non-rectifying
    - Openers: Somatostatin; β-adrenoceptor agonists
    - Blockers: Ba⁺⁺; Bradykinin
  - Atrial muscarinic-activated
    - Inward rectifying
    - Blockers: Ba⁺⁺; Cs⁺; 4-aminopyridine; TEA; Quinine
    - Structure: Tetramer of KCNJ3 & KCNJ5

Subunits: Molecular families

KCN types
A; B; C; D;
E; F; G; H;
J; K; M; N;
Q; S; T; V

Voltage-gated K⁺ channels (Kv)
- 6 transmembrane domains
- Activated by depolarization
- Present in both excitable and nonexcitable cells
- Functions
  - Regulate resting membrane potential
  - Control of the shape and frequency of action potentials
- α subunits: 2 types
  - Functional by themselves
  - Electrically silent: Modulate activity of functional α subunits
- Types
  - KCNA (Shaker)
    - General
      - Fast K⁺ channels
      - KCNA 1, 5 & 6 genes located in cluster on Chromosome 12p13
      - Form channels that are determinants of excitability of mammalian axons & nerve terminals
    - KCNA1 (Kv1.1) ³¹
      - Location
        
        Presynaptic & Juxtaparanodal axon membranes
        
        Present on dendrites
      - Channels with K_v1.1 subunits usually heterotetramers with K_v1.2 or K_v1.4 subunits
      - Mostly closed at resting membrane potential
      - Lower activation threshold & Faster onset rate than other members of K_v1 family
      - Rapid activation kinetics: Slower than fast Na⁺ channels
      - Delayed rectifier
      - Limits axonal hyperexcitability after action potentials
      - Edited by human adenosine deaminase acting on RNA 2 (ADAR2; ADARB1)
      - Expressed in interneurons, including basket cells of cerebellum
      - Disease: Episodic Ataxia/Myokymia Syndrome (EA1)
    - KCNA2 (Kv1.2)
      - Heterotetramer of potassium channel proteins
      - Location on axons: Presynaptic & juxtaparanodal
      - Molecular localizations
        
        N-terminus: Role in determining rate of channel inactivation
        
        Tail: Role in modulation of channel activity and/or targeting of the channel to specific subcellular compartments
        
        Segment S4: Probably voltage-sensor
      - Delayed rectifier: Mediates voltage-dependent potassium ion permeability of excitable membranes
      - Binds PDZ domains of DLG1, DLG2 & DLG4
      - Colocalizes with
        
        Kv1.1 on neocortical pyramidal cell dendrites
        
        Caspr2 at juxtaparanodes
      - Diseases
        
        Epileptic encephalopathy, Early onset 32 (EIEE32) : Leu298Phe mutation; Dominant
        
        Ataxia + Myoclonic epilepsy: Arg297Gln mutation; Dominant
        
        Hereditary spastic paraparesis, complex: Arg294His; Dominant
        Pingu mouse: Ile402Thr mutation
    - KCNA3 (Kv1.3)
      - Tissues: Skeletal muscle; Lymphocytes
      - Action: Delayed rectifier
      - T-cell functions
        
        Regulation of T cell membrane potential & cell volume
        
        Control of amplitude and duration of the Ca⁺⁺ signal during first steps of activation
        
        Channel activity regulated by glutamate
    - KCNA4 (Kv1.4)
      - Location: Presynaptic & Axonal & Fetal skeletal muscle
      - Type A rapidly inactivating
      - Antibodies present in some MG patients
    - KCNA4L
    - KCNA5 (Kv1.5)
      - Locations: Heart & Insulinoma
      - Function: Atrial-specific, ultra-rapid delayed rectifier K⁺ current, I(Kur)
      - Interacts with FHL1
      - Disease: Atrial fibrillation, familial 7
    - KCNA6 (Kv1.6) : Brain; Delayed rectifier
    - KCNA7
    - KCNA8 & KCNA9: see KCNQ1
    - KCNA10
    - KCNAB1 : β1 subunit (Kv-β-1.1)
      - Modulates gating properties & amplitudes of Shaker channels
      - β3 subunit from alternate splicing of this gene
    - KCNAB2 : β2 subunit (Kv-β-1.2)
    - KCNAB3
  - KCNB (Shab)
    - KCNB1 (Kv2.1)
      - Locations: Soma; Proximal dendrite
      - Associates with: KCNG3, KCNG4, KCNV2
      - Disorder: Epileptic encephalopathy, early infantile, 26 (EIEE26), Dominant or de novo
    - KCNB2 (Kv2.2)
  - KCNC (Shaw): Delayed rectifier
    - KCNC: General function
      - Kv3 channels regulate synaptic transmission at parallel fiber-Purkinje cell synapse in cerebellum
      - Mice lacking Kv3.1 or Kv3.3 channels: Ataxic
    - KCNC1 (Kv3.1)
      - Locations: Brain, Skeletal muscle, Lymphocytes, Spleen
      - Disorder: Progressive Myoclonus epilepsy + Ataxia (EPM7; MEAK) (Recurrent de novo Arg320His mutation)
    - KCNC2 (Kv3.2) : Brain
    - KCNC3 (Kv3.3)
      - Brain locations
        
        Brainstem: Auditory & Sensory nuclei
        
        Cerebellum
        
        Forebrain
      - Cells: Inhibitory neurons; Colocalizes with parvalbumin
      - Functions: Rapidly repolarize action potentials; Support high-frequency firing in neurons
      - Disorder: SCA 13
    - KCNC4 (Kv3.4) : Brain, Skeletal muscle
  - KCND (Shal): Molecular components of subthreshold-activating A-type K⁺ currents
    - KCND1 (Kv4.1) : Brain
    - KCND2 (Kv4.2)
      - Locations: Brain (Distal dendritic; Post-synaptic), Heart, Aorta
      - Regulation or Modulation by
        
        Neuronal calcium sensor 1
        Dipeptidyl-peptidase-like protein-6 (DPPX)
        
        Disorder: CNS + Autonomic syndrome
      - Binds to Filamin C
    - KCND3 (Kv4.3) :
      - Cardiac ventricle transient outward potassium current I(to)
      - Disorders
        
        SCA19
        
        SCA22
        
        Brugada syndrome 9
  - KCNE
    - General
      - Components of slow voltage-gated channels
      - Structure: Small, single transmembrane domain-containing proteins
      - Channel function: Accessory subunits; Interact with & regulate activity of Kv channels
    - KCNE1 (minK protein)
      - Epithelial cell apical membrane
      - Codes for β subunit
      - Coassembles with KCNQ1 (KCNA8; KVLQT1) α subunit: Causes increased current amplitude
      - Forms slowly activating delayed rectifier K⁺ (I_Ks) channel
      - Diseases
        
        Jervell-Lange-Nielsen Syndrome
        
        Long QT Syndrome 5
    - KCNE2 (minK related peptide 1)
      - Disease syndromes
        
        Long QT syndrome 6
        
        Atrial fibrillation (ATFB4)
        
        Ventricular fibrillation
        
        Clarithromycin-induced arrhythmia
    - KCNE3
      - Interacts with α-subunit KCNQ1 in intestine crypt cells
      - KCNQ1/KCNE3 channel
        
        Related to cyclic AMP-stimulated intestinal Cl^- secretion
        
        ? Involved in secretory diarrhea and cystic fibrosis
      - Mutations may cause
        
        Hypokalemic periodic paralysis
        
        Brugada syndrome 6
    - KCNE4
      - High tissue levels: Heart, skeletal muscle & kidney
    - KCNE1L
      - Expressed in heart, skeletal muscle, brain, spinal cord, and placenta
      - Deleted in AMME contiguous gene syndrome
  - KCNF
    - KCNF 1 : Large transcript abundant in heart; Smaller one brain specific
  - KCNG
    - KCNG1
      - Large transcript abundant in placenta & brain
      - Smaller transcript in skeletal muscle
    - KCNG2
      - Expressed in myocardium
      - Subunits in delayed-rectifier type channels
      - ? Contribute to cardiac action potential repolarization
    - KCNG3 (Kv10.1)
      - Functions as γ subunit
      - Modifies Kv2.1 channel activity
      - Subcellular location: Plasma membrane
    - KCNG4 (Kv6.3)
      - Regulatory subunit
      - Coexpressed with Kv2.1
      - Expression activated by DLK1
      - Physiology
        
        Accelerates time course of activation
        
        Hyperpolarizes threshold for activation
        
        Hyperpolarizes voltage dependence of inactivation
      - Gene variants: May be linked to migraine
  - KCNQ family ¹⁰
    - General
      - Express M-current properties
        
        Low-threshold, noninactivating, voltage-dependent K⁺ current
        
        Slowly opening & closing: 100x slower than channels associated with action potentials
        Limits repetitive firing due to persistent depolarizing stimulus
      - Interactions: Can couple to M₁ muscarinic acetylcholine receptors
      - M-channel activity
        
        Partially active in range of neuronal resting membrane potential
        
        Further activated by membrane depolarizations
      - Inhibited by membrane receptors
        
        Muscarinic AChR activity; Dopamine; Serotonin; Glutamate; Peptides
        
        Receptors acting on G-protein receptors
      - General actions
        
        Oppose epileptic activity: Restrain repetitive neuronal discahrges
        
        Mediate transient increases in activity after release of ACh and other transmitters
      - Drug interactions
        
        Linopirdine: Blocker of M-channels; Promotes ACh release
        
        Retigabine: Opens M-channels
        
        BMS-204352: Activates KCNQ channels; May reduce infarct size
      - Sensory neuron expression: KCNQ2; KCNQ3; KCNQ5
      - Disorders
    - KCNQ1 (KCNA8; KVLQT1)
      - K⁺ current: Slow delayed rectifier
      - Auxiliary subunit: KCNE1
      - Tissues: Heart, Pancreas, Cochlea (stria vascularis)
      - Disorders
        
        LQT1 syndrome
        
        Jervell-Lange-Nielsen Syndrome
        
        Atrial fibrillation, Dominant (ATFB3)
        Short QT syndrome 2
        Type 2 diabetes associations
    - KCNQ2
      - Locations
        
        Brain: Somatodendritic pyramidal & polymorphic neurons; Cortex & Hippocampus
        
        Sympathetic ganglia
        
        Testis
      - Form M-channels with KCNQ3 & Calmodulin
      - Diseases
        
        Seizures, Benign Familial Neonatal (EBN1; BFNS1)
        
        Myokymia & Benign neonatal epilepsy
        
        Neonatal seizures, dyskinesia, myoclonus & ataxia (Epileptic encephalopathy (EIEE7))
        Ohtahara syndrome
        KCNQ2 channels absent at nodes of Ranvier: MAG neuropathy; POEMS
        Activated by: Retigabine, drug for treatment of seizures
    - KCNQ3 (K_v7.3)
      - Locations
        
        Brain: Somatodendritic pyramidal & polymorphic neurons; Cortex & Hippocampus
        
        Sympathetic ganglia
        
        Spleen
        
        Cochlea
      - Form M-channels with KCNQ2, KCNQ5 & Calmodulin
      - Disease: Benign neonatal epilepsy (EBN2)
    - KCNQ4
      - Locations
        
        Cochlea: Sensory outer, but not inner hair cells
        
        Vestibular organs
        
        Brainstem: Auditory nuclei
      - Disorder: Nonsyndromic sensorineural hearing loss, Dominant (DFNA2)
    - KCNQ5 (K_v7.5)
      - Locations
        
        Brain
        
        Sympathetic ganglia
        
        Skeletal muscle
      - Auxiliary subunit: KCNQ3
      - M-current
      - Disorders
        
        Epileptic encephalopathy, Intellectual disability; Dominant inheritance
        
        Mental retardation, autosomal dominant 46 (MRD46)
  - KCNS family
    - General
      - Voltage-gated, Delayed rectifier
      - Brain, Spinal cord, Retina
      - No K⁺ channel activity
      - Modulate activities of Kv2.1 (KCNB) & Kv2.2 α subunits
    - KCNS1 (K_v9.1)
      - Expressed in brain
      - No potassium channel activity by itself
      - Modulates activities of K_v2.1 (KCNB1) & K_v2.2
    - KCNS2 (K_v9.2)
      - Expressed in brain
      - No potassium channel activity by itself
      - Modulates activities of K_v2.1 (KCNB1) & K_v2.2
    - KCNS3 (K_v9.3)
      - Polymorphisms associated with airway hyperresponsiveness
  - KCNV family
    - KCNV1 (Kv8.1)
      - Modifies kinetics of KCNB channels
    - KCNV2 (Kv11.1)
      - Coexpressed with Kv2.1
      - Disease: Retinal Cone Dystrophy 3B with supernormal rod electroretinogram
  - Brain cyclic nucleotide gated K⁺ channels (BCNG) ²²
    - Types
      - HCN1
        
        Expression in brain
        
        Activate rapidly
        
        Large non-nociceptive sensory neurons: Fast, cAMP-insensitive Ih current
        Opioid-induced Tolerance
        Disruption: Impaired motor learning; Enhanced spatial learning & memory
        
        Disorder: Infantile epileptic encephalopathy (Dravet)
        
        De novo dominant mutations
      - HCN2 ²⁷
        
        Expression: Nerves, Brain & Heart
        
        Modulate action potential firing
        Small nociceptive C-fiber neurons: Ih currents; Forskolin sensitivity
        Disorders
        
        Absence epilepsy, Ataxia & Cardiac sinus node dysfunction
        
        Febrile seizures, familial, 2, Dominant
        Generalized epilepsy with febrile seizures plus, type 11
        
        Role in: Abnormal pain responses
        
        Peripheral HCN2 channels
        To Heat & Mechanical stimuli
        
        Associated with Na_v1.8 Na⁺ channels
        
        PGE₂ induced neurons in inflammatory thermal hyperalgesia
        
        PGE₂: Downstream target of nonsteroidal anti-inflammatory (NSAID) analgesics
        
        Opioid-induced Hyperalgesia
        Migraine pain
        
        May have effect on CNS myelin sheath length
      - HCN3
        
        Expression: Brain; None in heart or skeletal muscle
        Conducts potassium & sodium ions: 3:1 preference for potassium
        
        Activity not modulated by intracellular cAMP
      - HCN4
        
        Expression: Heart, brain (thalamus) & testis
        
        Activate slowly
        
        Deletion: Death during embryonic development; No sinoatrial node-like action potentials
        
        Diseases
        
        Brugada syndrome 8
        Sick sinus syndrome 2
    - Properties
      - Permeability
        
        Cations
        
        K⁺ 4x > Na⁺
        
        Current carried by Na⁺ ions at typical membrane voltages
        
        Anions: None
      - Activation
        
        Hyperpolarized membrane potentials
        
        Slow time course
        
        Sensitive to intracellular cyclic nucleotides
      - Modulated by: Cyclic nucleotides
      - Blockade by
        
        Extracellular: Cesium; Capsazepine (Blocker of vanilloid receptors)
        
        Intracellular: QX-314 (Lidocaine derivative); ZD7288 Bradycardiac agent)
      - Pacemakers: Generate rhythmic cellular activity
        
        h-currents (I_h)
        
        Allow cells to be rhythmically active over precise intervals of time
        
        Tissue location: Cardiac; Neuronal
      - Other functions
        
        Dendritic integration
        
        Temporal summation of distal synaptic inputs
        
        Dampens cellular responses to inhibitory synaptic input
        Allows rapid resumption of tonic firing
        
        Synaptic release
        
        Can facilitate neurotransmitter release
        
        Response to repetitive action potentials
        
        Primary sensory reception
        
        Expressed in taste cells: Receptors for sour taste
        Thermoreception
- External link: Chicago
Potassium channels: Inwardly rectifying (Kir)
- General properties
- General families
  - Kir2.0
    - Action: Strong rectification
    - Function: Maintenance & control of cell excitability
    - Interactions: Among all Kir2 channels; SAP97
  - Kir3.0 (GIRK)
    - KCNJ subtypes: 3, 5, 6, 9
    - G-protein gated
    - Tetramers form K_G channels
    - Expressed throughout CNS
    - Acetylcholine-responsive inward rectifier composed of Kir3.1 & Kir3.4
  - Kir1.0/4.0: K+ transporters
  - Kir5.1
    - Homomeric assembly with PSD-95
    - Related to PKA-mediated signalling
  - Kir6
    - ATP sensitive
    - Associates with sulfonylurea receptors
  - Kir7
    - Very low single channel conductance
    - Low sensitivity to block by external Ba⁺⁺ and Cs⁺
    - No dependence of inward rectification properties on internal blocking Mg⁺⁺
    - Helps to set membrane potential
- Kir Types: Large family
  - KCNJ1 (Kir1.1):
    - Highest tissue levels: Kidney & Pancreas islets
    - Activation: Internal ATP
    - Blockade: External Ba⁺⁺
    - Disease: Bartter syndrome (Antenatal)
  - KCNJ2 (Kir2.1)
    - Tissue localization: Brain, Heart, Skeletal muscle, Lung, Kidney, Placenta
    - Strong inward rectifier
    - Channel compositions
      - Channels are often homotetramers
      - Subunit associations: Other Kir2; SAP97
    - Polarized distribution: Enables channels to transport K⁺ ions to appropriate regions
    - Role
      - Generation of action potential waveform + Excitability in muscle & neural tissue
      - Prevents excessive loss of K⁺ during plateau phase of cardiac action potential
      - Allows outward K⁺ flux during terminal repolarization & diastole
      - Development: Myoblast fusion; Bone morphogenesis
    - G-protein enhanced current
    - Blocked by Ba⁺⁺ or Cs⁺
    - Diseases
      - Andersen syndrome
      - Long QT syndrome 7 (LQT7)
      - Short QT syndrome 3 (SQT3)
      - Atrial fibrillation, familial 9 (ATFB9)
  - KCNJ3 (Kir3.1)
    - Subunit associations
      - KCNJ5, KCNJ6 & KCNJ9
      - Homotetramers do not form functional channels
    - Muscarinic & G-protein linked
    - Role: Heartbeat regulation
  - KCNJ4 (Kir2.3)
    - Subunit associations: Other Kir2; SAP97
    - Polarized distribution: Enables channels to transport K⁺ ions to appropriate regions
    - Modulated by arachidonic acid
    - Tissue localization: Heart; Skeletal muscle; Brain (Hippocampus)
  - KCNJ5 (Kir3.4)
    - Subunit associations: KCNJ3, KCNJ6
    - Tissue localization: Pancreas; Heart
    - Disorders
      - Congenital long QT syndrome, Dominant (LQT13)
      - Periodic paralysis
      - Hyperaldosteronism, familial, type III
    - Knockouts: Channel role in vagal regulation of heart rate & Spatial memory
  - KCNJ6 (GIRK2; KCNJ7) (Kir3.2)
    - Localization: Cerebellum
    - Associates with KCNJ9
    - Mediate inhibitory effects (outward currents) of opioids
    - Disorders
      - Keppen-Lubinsky lipodystrophy syndrome (KPLBS)
      - Weaver mouse (Gly156Ser)
    - Knockouts: Seizures & Ethanol-induced behaviors
  - KCNJ8 (Kir6.1)
    - Function: Regulation of vascular tone
    - Controlled by G-proteins & ATP
    - Knockout: Sudden death; Spontaneous ST elevation; Atrioventricular block
  - KCNJ9 (Kir3.3)
    - Associates with KCNJ6
    - Mediate inhibitory effects (outward currents) of opioids with Kir3.2
    - Knockouts: Neuron membrane depolarization
  - KCNJ10 (Kir1.2; Kir4.1)
    - Forms heterodimer with KCNJ16
    - ATP-dependent
    - Location: Glial; Muller cells (Retina); Kidney; Gastric parietal cells
    - Subcellular
      - Polarized distribution: Enables channels to transport K⁺ ions to appropriate regions
      - Subcellular clustering associated with Dystrophin isoform dp71
      - Predominantly expressed in membranes adjacent to basement membranes
      - Laminin is necessary for surface expression of Kir4.1
      - Co-localizes with aquaporin-4 water channel in retinal glial cells
    - Functions
      - CO₂ chemoreception
      - Brain: ? Glial K⁺ buffering
      - Endocochlear potentials
      - Renal: K⁺ secretion
    - Disorders
      - SeSAME
      - Dogs (Jack Russell Terriers & Related): Spinocerebellar Ataxia with Myokymia or Seizures (Recessive)
    - Knockout
      - Spinal hypomyelination
      - Loss of endocochlear potentials & oligodendrocyte K⁺ conductance
  - KCNJ11 (Kir6.2)
    - Associates with sulfonylurea receptor (SUR1)
    - Controlled by G-proteins
    - ATP-sensitive
    - Expression: Ubiquitous
    - Function: Mediates glucose homeostasis; Glucose-stimulated insulin secretion
    - Diseases
      - Hyperinsulinemic hypoglycemia 2 (HHF2) : Unregulated insulin secretion
      - MODY13
      - Diabetes, permanent neonatal 2 (PNDM2)
      - Diabetes mellitus, transient neonatal, 3
      - May contribute to Type 2 diabetes: E23K polymorphism
      - Neonatal diabetes, transient or permanent
      - DEND: Developmental delay, Epilepsy & Neonatal Diabetes
        
        Treatment with sulfonylurea
      - Mouse: Somatosensory dysfunction & Axon loss
  - KCNJ12 (Kir2.2)
    - Channels formed by homotetramers or associations with other Kir2
    - ATP sensitive
    - Role in action potential waveform and excitability of neurons & muscle
  - KCNJ13 (Kir7.1)
    - Localization: GI; Neurons; Kidney; Retinal pigment epithelium
    - Mild inwardly rectifying K⁺ current: Inverse dependence of conductance on [K⁺]_o
    - Function: K⁺ conductance of the Retinal pigment epithelium apical membrane
    - Disorders
      - Leber congenital amaurosis 16, Recessive (LCA16)
      - Snowflake vitreoretinal degeneration, Dominant (SVD)
  - KCNJ14 (Kir2.4)
    - Cranial nerve motoneurons in general somatic & special visceral motor cell columns
  - KCNJ15 (Kir4.2)
    - Localization: Kidney; Pancreatic β cells; Brain
    - Forms heterodimer with KCNJ16
    - Susceptibility gene in Asian patients with Type 2 Diabetes Mellitus: OR = 2.5; Exon 4 (C566T)
  - KCNJ16 (Kir5.1)
    - Tissues: Brain, Kidney & Pancreas
    - Functional channels formed with: KCNJ15; PSD-95
    - Associated with CO₂ chemoreception
    - Disease: Hypokalemic tubulopathy & Deafness (HKTD) : Gitelman-like
  - KCNJ18 (Kir2.6)
    - Inwardly rectifying potassium channel activity
    - Strong homology with KCNJ12
    - Disease: Thyrotoxic hypokalemic periodic paralysis
  - KCNJN1
    - Inhibitor of KCNJ12 (Kir2.2)
- Human ether-a-go-go (HERG; KCNH) : Related to cyclic nucleotide-gated cation channels
  - KCNH1 (Kv10.1)
    - Expressed at onset of human myoblast differentiation
  - KCNH2 (Kv11.1)
    - Channel activation accelerated by K⁺ Channel regulator 1
    - Diseases
      - Long-QT 2 syndrome
      - Short QT syndrome 1
  - KCNH3 (BEC1)
    - Locations
      - Cerebral cortex: Layer II to layer VI; Cell bodies of neurons with pyramidal shapes
      - Hippocampus: CA1 & CA3 pyramidal cell body layers; Granule cell layers of dentate gyrus
    - Electrophysiology: Voltage-gated outward current with a fast inactivation component
  - KCNH4 (BEC2)
    - Locations: Brain specific
      - Striatal regions: Putamen & caudate nucleus
      - Lower levels in cerebral cortex & hippocampus
    - Electrophysiology
      - Voltage-gated outward current
      - No fast inactivation component
  - KCNH5
    - Location: Brain, Adult
    - Disease: Developmental & Epileptic Encephalopathy 112 (DEE112)
  - KCNH6 (HERG2; Kv11.2)
    - Time constant for deactivation: Voltage dependent; Decreased with more negative potentials
    - Deactivation kinetics slower than KCNH7
  - KCNH7 (HERG3; Kv11.3)
    - Time constant for deactivation: Voltage dependent; Decreased with more negative potentials
    - Fast deactivation kinetics
  - KCNH8
    - Locations: Forebrain; Testis
    - K⁺ current at depolarizing voltages
      - Outward
      - Slowly activating
      - Noninactivating
      - Slowly deactivating
KCNK family: 4 transmembrane domains; 2 pore (P) (tandem pore) domains;
- General
  - "Leak" channels: Goldman-Hodgkin-Katz (GHK) outward rectification
- KCNK1 (TWIK) :
  - Weakly inward-rectifying current
  - Control of background K⁺ membrane conductances
  - Expressed in CNS
- KCNK2 (TREK1) ³⁶
  - Outward rectifying
  - Sensitive to extracellular K⁺ & Na⁺
  - Expressed in CNS
  - Activation: Halothane (Volatile anesthetics); Stretch; Polyunsaturated fatty acids, Lysophospholipids
  - Inhibition: Neurotransmitters that increase intracellular cAMP or activate Gq signaling pathway
  - Also forms heterodimeric channels with TRESK
  - Function: Mechanotransduction
  - Disorders
    - POPDC mutations
    - Migraine & Pain related
- KCNK3 (TASK)
  - Inhibited by extracellular acid: ? Role in cell response to extracellular pH
  - Activated by Halothane
  - Disease: Pulmonary hypertension (PPH4)
- KCNK4 (TRAAK) ³⁴
  - Expressed in neural tissues
    - Nodes of Ranvier: PNS & CNS
  - Currents: K⁺ selective, instantaneous, noninactivating, & outwardly rectifying
    - Contributes to 'Leak' K+ current in axon conduction
    - Hyperpolarizes resting membrane potential
    - Increases Na⁺ channel availability for action potential propagation
  - Potentiated by polyunsaturated fatty acids, e.g. arachidonic acid
  - Function: Mechanotransduction
  - Disease: Facial dysmorphism, Hypertrichosis, Epilepsy, Intellectual disability/developmental delay & Gingival overgrowth (FHEIG)
- KCNK5 (TASK2)
  - Location: Renal, Neural
  - Two gates: Controlled by intra- & extra-cellular stimuli
  - Functions & Actions ³⁵
    - Generates pH-gated leak-type K⁺ currents
    - Control cellular electrical excitability
    - Involved in breathing regulation: Chemosensory neurons of brainstem retrotrapezoid nucleus
    - pH homeostasis: By kidney proximal tubule cells
  - Control of function
    - Channel activation by: Intracellular & extracellular alkalization
    - Inhibited by: Extracellular acid
- KCNK6 (TWIK2; TOSS) : Many tissues; Eye ganglion cells & inner nuclear layer
- KCNK7 (TWIK-1-like)
  - Expressed in CNS
  - No channel activity when expressed alone
- KCNK8
  - Expressed in eye, lung, & stomach
  - No channel activity when expressed alone
- KCNK9 (TASK3 protein)
  - Family: Two-pore domain potassium (K2P) channel
  - Paternally imprinted gene: Only maternal allele is expressed
  - Expression: ? Selectively in cerebellum or Widely expressed
  - Current
    - Time-independent, noninactivating K⁺-selective
    - Stabilization of resting membrane potential of excitable & non-excitable cells
    - Sensitive to changes in extracellular pH: Inhibited by extracellular acid
    - Blocked by barium, quinidine, and lidocaine
    - Inhibited by activated G-protein-coupled receptors (GPCRs)
  - Subunits of heteromeric channels in orexin (hypothalamic) neurons that are sensitive to glucose
  - Oncogenic: Over-expressed in human carcinomas
  - Disorder: Birk-Barel Mental Retardation-Dysmorphism Syndrome (BIBARS)
    - Nosology: KCNK9 imprinting syndrome (KIS)
    - Genetics
      - Inheritance: Dominant/de novo
      - Mutations: Heterozygous; Arg131, Gly236Arg & other missense
    - Clinical
      - Onset age: Birth
      - Neuromuscular
        
        Weakness: Diffuse & Bulbar
        
        Tongue fasciculations
        
        Areflexia
      - Possible treatments
        
        Pyridostigmine
        
        Mefenamic acid
    - Laboratory
      - Muscle pathology: Chronic denervation
      - EMG: Denervation
- KCNK10 (TREK2)
  - Rapidly activating & noninactivating outward rectifier K⁺ channel currents
  - Stimulation
    - Strongly by polyunsaturated fatty acids: Arachidonic acids
    - Cell membrane stretch
    - Intracellular acidification
    - Inhalational general anesthetics
    - Transiently activated by riluzole
  - Function: Mechanotransduction
- KCNK12 (THIK-2; Tandem pore domain Halothane Inhibited K⁺ channel)
  - Expressed in brain & kidney
  - No functional current detected
  - Inhibited by Halothane
- KCNK13 (THIK-1)
  - Ubiquitous expression: High in olfactory, septal, hypothalamic & thalamic nuclei of brain
  - Weak inward rectification
  - Current enhanced by arachidonic acid
  - Current inhibited by halothane
- KCNK14
- KCNK15
  - Expression in heart, skeletal muscle, testis, thyroid gland, adrenal gland, salivary gland, pancreas
- KCNK16 (TALK-1)
  - Channel properties
    - K⁺ currents: Outward rectifying; Lost by elevation of extracellular K⁺
    - Activated at alkaline pH
    - Current sensitive to barium, quinine & volatile anesthetics: Inhibited by halothane
  - Distribution: Pancreas
- KCNK17 (TALK2; TASK4)
  - Channel properties
    - K⁺ currents: Outward rectifying; Lost by elevation of extracellular K⁺
    - Activated at alkaline pH
    - Current sensitive to barium ± quinine & volatile anesthetics
  - Distribution: Liver, lung, placenta, pancreas, small intestine, aorta
- KCNK18 (TRESK; TRIK) ³⁶
  - Channel properties
    - Outward rectifying: Produces rapidly activating outward rectifier K⁺ currents
    - May function as background K⁺ channel: Sets resting membrane potential
    - Inhibited by: Arachidonic acid; Other naturally occurring unsaturated free fatty acids.
    - Channel activity enhancement: Volatile anesthetics (isoflurane)
    - Also forms heterodimeric channels with TREK1
  - Disease: Migraine ± Aura 13, Susceptibility (MGR13)
KCNM: Ca⁺⁺ sensitive; Large conductance channels (MaxiK; BK)
- General
  - Respond to
    - Increased intracellular Ca⁺⁺ ion concentrations
    - Membrane depolarization
  - Subunits
    - 4 alpha subunits & 4 optional auxiliary beta subunits
    - α-subunit: Pore forming; KCNMA1
    - β-subunit: Modulatory
  - Sensitive to peptide toxins: Charybdotoxin, Iberiotoxin; Bind to β-subunit
  - Functions
    - Play a role in leukocyte-induced microbial death
    - Translate Ca⁺⁺ signals to vasoregulation
- KCNMA1 : Ca⁺⁺ activated; Large conductance
  - Pore forming component of KCNM channels
  - Multiple isoforms through alternative splicing
  - Mediated current
    - Fast
    - Ca⁺⁺ activated K⁺ current
  - 17-β-estradiol binds to β subunit
  - May play role in cochlear frequency selectivity
  - Fetal skeletal muscle
  - Diseases
    - Generalized epilepsy + Paroxysmal dyskinesia 3 (PNKD3)
      - Attacks: Brief; Multiple/Day
      - Dyskinetic movements: Tongue & Jaws
      - Behavioral arrest
      - Loss of postural reflexes with focal body stiffness & falling
      - Rapid recovery without post-ictal drowsiness
    - Cerebellar atrophy, Developmental Delay, Seizures (CADEDS)
    - Liang-Wang Syndrome (LIWAS)
    - Epilepsy susceptibility 16 (EIG16)
  - Null mice: Ataxia & Vascular (smooth muscle) dysfunction
- KCNMB1
  - Smooth muscle, Skeletal muscle (Fetal), Brain (Hippocampus, Corpus calosum)
- KCNMB2 : Ca⁺⁺ activated; Large conductance
  - Subunit induces fast inactivating currents that can be increased by voltage & intracellular Ca⁺⁺
- KCNMB3
- KCNMB4
KCNN: Calcium-activated, Small/Intermediate conductance
- KCNN1 (SK1)
  - Brain, Heart
  - Small conductance, Ca⁺⁺ activated
  - Apamin sensitive
- KCNN2 (SK2)
  - Brain, Adrenal gland, Retinal ganglion cells & neurons
  - Apamin, Scyllatoxin & Tubocurarine sensitive
  - Charybdotoxin insensitive
- KCNN3 (SK3)
  - Small conductance, Ca⁺⁺ activated
  - Intermediate apamin sensitivity
  - Ca⁺⁺ activated
  - Contains 2 CAG repeat sequences:
    - Polymorphisms
    - Long CAG sequences: Not causative but ? Associated with sporadic ataxia ¹³
  - Brain, Heart, Skeletal muscle (Embryonic), Liver
  - Endothelial SK3: May contribute to exercise hyperemia
  - Disorder
- KCNN4 (SK4)
  - T-lymphocytes; Colon, Smooth muscles, RBCs, Neurons
  - Intermediate conductance
  - Ca⁺⁺ activated
  - Blocking agents: Clotrimazole; Charybdotoxin
  - Major pathway for cell shrinkage via KCl and water loss in sickle cell disease
KCNT family: Intermediate-conductance calcium-activated
- General
  - Activated by intracellular Na⁺ & Cl^-
  - Inhibited by intracellular ATP
- KCNT1 (Slack)
  - Expression
    - Moderate to high in all tissues
    - Highest in liver & brain
    - Lowest in skeletal muscle
  - Interacts with: Slo subunits
  - Disorders: Epilepsy
    - Frontal lobe epilepsy, nocturnal, Dominant
    - Malignant migrating partial seizures of infancy (EIEE14)
- KCNT2 (Slick)

KCTD (Potassium channel tetramerization domain-containing proteins)

KCTD1
- Scalp-ear-nipple syndrome
KCTD2
KCTD3
KCTD4
KCTD5
KCTD6
KCTD7
- Progressive myoclonic epilepsy 3 (EPM3)
KCTD8
KCTD9
KCTD10

KCTD11
KCTD12
KCTD13
KCTD14
KCTD15
KCTD16
KCTD17
KCTD18
KCTD19
KCTD20
KCTD21

SUR (High-affinity sulfonylurea receptor)
- SUR1 (ABCC8) : Pancreatic islets
- SUR2 (ABCC9)
  - 2A: Heart
  - 2B: Brain, Liver, Skeletal & Smooth muscle, Bladder
Plasmolipin
- Brain (myelin) & Kidney
- Forms K⁺ specific, voltage-dependent channels when added to lipid bilayers

Disorders of K⁺ Channels

Toxins ¹
- Organic: 4-aminopyridine; Tetraethyl-ammonium
- Polypeptide
  - Agitoxin-2
  - Apamin
  - Charybdotoxin
  - Dendrotoxin
  - Tityus toxin K-α
  - Tarantula toxins
    - Voltage sensor toxin 1 (VSTX1; Tarantula venom)
      - Inhibits KvAP voltage dependent channel: Partitions in lipid membrane, then binds to receptor ²⁰
    - Hanatoxin 1 : Binds to Kv2.1 & Kv4.2; Alters gating energetics
    - Hanatoxin 2 : Binds to Kv2.1; Blocks K⁺ currents
- Barium
- Aldosterone-like: Licorice (Glycyrrhizic acid); Carbenoxolone (Glycyrrhetinic acid)
- Volatile substances: Toluene
- Ethanol
- Cottonseed oil (with low dietary K+)
- Bergamot oil (Bergapten; 5-methoxypsoralen): Earl Grey tea
Immune
Hereditary
- Hypokalemic periodic paralysis: KCNE3
- Andersen syndrome: KCNJ2 (Kir2.1)
- Bartter syndrome (Hypokalemic alkalosis with hypercalciuria), type 2
  ● Inward rectifing K⁺ channel, Subfamily J, Member 1 (KCNJ1)
  ● Also caused by mutations in Na⁺/K⁺/Cl^- transporter-2 (SLC12A1) and Cl^- channel (CLC-Kb)
- Cardiac: Long-QT Syndromes
  - KVLQT (LQT1 syndrome): Voltage gated K⁺ channel (KCNQ1)
    - Jervell & Lange-Nielsen Syndrome : Recessive
    - Romano-Ward Syndrome : Dominant
  - HERG (LQT2 syndrome): Inward rectifying K⁺ channel (KCNH2)
  - LQT4 : Chromosome 4q25-q27; ? gene
  - Jervell & Lange-Nielsen Syndrome : Recessive
    - 2 genetic causes
      - K⁺ Voltage gated channel, ISK-related subfamily, Member 1 (KCNE1)
      - KCNQ1 (KCNA8; KVLQT1) K⁺ channel
    - Long-QT syndrome & Congenital hearing loss
    - Mechanism of arrhythmia
      - Accelerate channel incativation
      - Delays myocardial repolarization
  - Long QT syndrome 5: KCNE1
  - Long QT syndrome 6: KCNE2 (minK related peptide 1)
    - Ventricular fibrillation
    - Clarithromycin-induced arrhythmia
- Cardiac: Other
  - Atrial fibrillation, Dominant : KCNQ1
  - Short QT syndromes
  - Pulmonary hypertension: KCNK3
- Neural
  - Ataxia
    - Episodic Ataxia/Myokymia Syndrome: KCNA1 (Voltage gated K⁺ channel; Kv1.1)
    - SCA 13: KCNC3 (Kv3.3)
  - Epilepsy
    - SeSAME: KCNJ10
    - Benign neonatal epilepsy: KCNQ2 : & KCNQ3
      - Mutations cause reductions in size of K⁺ currents
    - Generalized epilepsy + Paroxysmal dyskinesia: KCNMA1
    - Myokymia & Benign neonatal epilepsy: KCNQ2
    - Epileptic encephalopathy, early infantile, 26 (EIEE26) : KCNB1
    - Frontal lobe epilepsy, nocturnal, Dominant: KCNT1
    - Malignant migrating partial seizures of infancy, De novo Dominant (EIEE14) : KCNT1
    - Progressive myoclonic epilepsy (EPM3) & Opsoclonus-Myoclonus: KCTD7
    - Facial dysmorphism, Hypertrichosis, Epilepsy, Intellectual disability/developmental delay & Gingival overgrowth (FHEIG) : KCNK4
  - Other CNS
    - Birk Barel mental retardation dysmorphism syndrome : KCNK9
    - Zimmermann-Laband syndrome 3 (ZLS3) : KCNN3
    - ?? Paroxysmal Choreoathetosis/Spasticity
- Hyperinsulinemic hypoglycemia of infancy: Familial persistent
  - Subunit of ATP-sensitive pancreatic β-cell K⁺ channel (ABCC8)
    - High-affinity sulfonylurea receptor (SUR1)
  - Inwardly rectifying K⁺ channel: BIR subunit (KCNJ11) ; Pancreatic β-cell
- Non-syndromic hearing loss, Dominant: KCNQ4
- Cone dystrophy with supernormal rod electroretinogram: KCNV2 (Kv11.1)
- Weaver mouse: G-protein coupled, inward rectifing K⁺ channel (KCNJ6)
  - Human homologue gene at Chromosome 21q22.1

MAGNESIUM

Magnesium

Renal associations
- Dialysis: Associated with high levels
- Magnesium toxicity: More common when magnesium parenterally administered in renal failure
Vascular calcification: Correlates inversely with serum magnesium levels
Tendon reflexes: Reduced by high magnesium levels
Myasthenia gravis: May produce exacerbation
Acute flaccid paralysis
- May occur with high magnesium levels
- May be assocaited with NMJ disorder
Oxaliplatin neurotoxicity: Ca⁺⁺ & Magnesium may reduce toxicity

Hypomagnesemia

Clinical
- Seizures
- Tetany
- Paresthesias
- Weakness
Genetic syndromes
- Primary hypomagnesemia
  ● Claudin 18; Chromosome 3q; Recessive
- Hypomagnesemia with secondary hypocalcemia
  ● TRPM6 ; Chromosome 9q22; Recessive
- Magnesium & Potassium depletion (Gitelman syndrome)
  ● Na-Cl cotransporter (SLC12A3) ; Chromosome 16q13; Recessive
- Hypomagnesemia 2, Renal (HOMG2)
  ● FXYD2 ; Chromosome 11q23; Dominant

Gitelman Syndrome (Familial Hypokalaemia�Hypomagnesemia)

³⁷
● Na-Cl cotransporter (SLC12A3)

; Chromosome 16q13; Recessive

Epidemiology
- 2.5 to 25/100,000
- More common in Asians
Genetics
- Mutations: Inactivating
- Similar phenotypes
  - MTTI, MTTF, CLCNKB, KCNJ10, KCNJ16, ATP1A1, FXYD2, HNF1B
SLC12A3 protein
- Sodium chloride cotransporter (NCC): Thiazide-sensitive
- Renal: Distal convoluted tubule; Na⁺ transporter
- Mutations: Impaired NCC-mediated Na⁺ reabsorption
Clinical: Varied
- Onset of symptoms with
  - Vomiting
  - Gastroenteritis
- Paraesthesia
- Weakness
  - May be episodic & related to hypokalemia
- Rhabdomyolysis
- Fatigue
- Salt craving
- Dizziness
- Enuresis
- Other
  - Chondrocalcinosis
  - Ventricular arrhythmia
  - Seizures
  - Ataxia
  - Tetany
- Avoid
  - Proton pump inhibitors
  - Antimicrobials (Aminoglycosides)
  - Antiretrovirals
  - Amphotericin
  - Thiazides
  - Xanthine
  - Verapamil
  - Insulin in high doses with glucose
Laboratory
- General: Salt-losing renal tubulopathy
- Hypokalemia
- Hypomagnesemia
- Calcium: May be low in blood & urine
- Serum renin: High
- Metabolic alkalosis
- Hypoparathyroidism

ANION CHANNELS, EXCHANGERS & TRANSPORTERS

Anion exchange proteins:
- SLC4A1 (AE1) : Erythrocyte band 3 protein
  - Major integral glycoprotein in erythrocyte membrane
  - Polymorphisms determine Diego blood group
  - Diseases: Spherocytosis; Ovalocytosis; Renal tubular acidosis; Hypokalemic periodic paralysis
- Other
  - SLC4A2 : Anion exchanger; ? Choroid plexus, GI & Other
  - SLC4A3
    - Anion exchanger; Cardiac & Brain
    - Short QT syndrome 7
  - SLC4A4 : Na Bicarbonate cotransporter; Renal; Renal tubular acidosis, glaucoma, cataracts, & band keratopathy
  - SLC4A5 : Na Bicarbonate cotransporter; Pancreas
  - SLC4A6 : Na Bicarbonate cotransporter; Retina
  - SLC17A5 (Sialin) : Salla syndrome (Sialic acid storage)
  - SLC26A3: Down-regulated in adenoma (DRA)
    - ? Sulfate transporter
    - Congenital chloride diarrhea
  - SLC26A4: Transporter of Chloride & Iodide
    - Non-syndromic deafness, congenital (DFNB4)
    - Pendred syndrome
    - Enlarged vestibular aqueduct syndrome
Voltage dependent anion selective channel proteins (VDAC)
- Location: Outer mitochondrial membrane ± Plasma membrane
- Functions
  - Channels for small hydrophilic molecules
  - Translocation of adenine nucleotides through outer mitochondrial membrane
  - BCL2 proteins bind to VDAC: Regulate mitochondrial membrane potential & release of cytochrome c during apoptosis
  - Mitochondrial binding site for: Hexokinase (HK1); Glycerol kinase
- VDAC1 (Porin) ⁴²
  - Sucellular location: Mitochondrial membrane
  - Pathway for movement of adenine nucleotides through outer mitochondrial membrane
  - Mitochondria
    - Binding site for hexokinase & glycerol kinase
    - Energy metabolism
    - Membrane permeability
    - Calcium balance regulation
  - Programmed cell death pathways: Facilitation
  - Disease related: VDAC1 binds to
    - Misfolded SOD1
    - Hexokinase 1
- VDAC2
  - Open conformation: At low or zero membrane potential; Weak anion selectivity
  - Closed conformation: At potentials above 30-40 mV; Cation-selective
- VDAC3
  - High expression in testis
  - Sucellular location: Mitochondrial membrane
  - Null mice
    - Sperm motility: Reduced
    - Muscle: Mitochondria abnormally shaped, Respiratory chain complex activity reduced
- VDAC4
Organic anion transporter (OATP)
- Na⁺-independent transport of organic anions, e.g. bile acids
Canalicular multispecific organic anion transporter (cMOAT)
- Dubin-Johnson Syndrome
Sulfate anion transporter

CATION CHANNELS

Cyclic Nucleotide-Gated

CNG channels
- α1 subunit (CNGA1)
  - Localization: Rod photoreceptors
  - Integral membrane protein
    - Mediates visual signal transduction
    - Cyclic GMP is 2nd messenger: Activates cation channel ® Rod photoreceptor depolarization
    - Polymerizes with CNGB1
    - Stimulation: Darkness opens channels to Na⁺ & Depolarizes photoreceptors
    - Inhibition: Light activates cGMP causing channel closure & Hyperpolarizes photoreceptors
  - Disease: Retinitis pigmentosa
- α2 subunit (CNGA2) : Olfactory
  - Activated by 3 molecules of cATP
  - Channel ions: Na⁺ & Ca⁺⁺
  - Odorant-evoked activity
  - Null mice: Fail to mate or fight
- α3 subunit (CNGA3)
  - Localization: Testis; Kidney; Heart; Eye
  - Disease: Rod monochromacy (Total color blindness; Achromatopsia 2 )
- α4 subunit (CNGA4)
  - Olfactory signaling: Mediates negative feedback; Allows rapid adaptation
- β1 subunit (CNGB1) : Retina with CNGA1
- β3 subunit (CNGB3) : Achromatopsia 3 (Pingelapese blindness )
- Brain CNG 1 & 2: Voltage gated K⁺ channels
Ca⁺⁺ transporting ATPase
ATP-gated Cation Channel (ACC) Family (P2X receptors)
Cu⁺⁺ transporting ATPase 7
- Wilson's : β polypeptide
- Menkes : α polypeptide
- Occipital horn syndrome : α polypeptide
K⁺/H⁺ ATPase: B₁₂ deficiency
Hyperpolarization-activated cyclic nucleotide-gated K⁺ channels (HCN)

Cation Leak

Sodium leak channel, nonselective (NALCN)

Properties
- Voltage-independent ion channel
- Produces Cs⁺ & Tetrodotoxin-resistant background Na⁺ leak conductance
- Regulates: Neuronal excitability
- Expressed in: Brain & Spinal cord
Disease: Infantile Neuroaxonal Degeneration with Facial Dysmorphism (INNFD)

PROTON-GATED ION CHANNELS: Neural

General
- Two-transmembrane-domain proteins
- Related to putative mechanosensory DEG/ENaC channels
- Gated by reductions in extracellular pH
- Most subtypes expressed in DRG: ASIC1b & ASIC3 have preferential expression in sensory ganglia
Types
- ACCN1: Mammalian degenerin homologue (MDEG-1; BNC1; ASIC-2) : Na⁺ channel
  - Cation channel
  - Inhibitor: Amiloride
  - Excited by: Hair movement; Acid, ASIC2b with ASIC-3
  - Physiologic function
    - Role in: Mechanically stimulated graded potential in axonal receptors
    - Nociception: Acid-induced cardiac pain
    - Not related to detection of noxious mechanical stimuli
  - Location
    - Palisades of lanceolate nerve endings around hair follicles
    - Dorsal root ganglion cells: Large & Small
    - Abundant in brain neurons
  - ASIC-2 deficient mice
    - Rapidly adapting mechanoreceptors: Reduced sensitivity to hair movement
    - Some reduced sensitivity in response of slowly adapting mechanoceptors
- ACCN2: Acidic sensing ion channel (ASIC-1)
  - 2 variants
    - Alpha (ASIC-α): Expressed widely in brain
    - Beta (ASIC-β): Expressed only on sensory neurons
  - Inhibitor: Amiloride
  - Ion permeability: Na⁺ > Ca⁺⁺ > K⁺
  - Activation: Transient (Rapidly inactivating); By rapid extracellular acidification
  - Brain neurons
  - Disease
    - Focal ischemia or acidosis: May play a role in cell injury
    - ASIC1A & H⁺-gated currents: May contribute to fear & anxiety disorders
- ACCN3: Dorsal root acidic sensing channel (DRASIC; ASIC-3) :
  - Form hetermultimeric channels
  - Location
    - DRG neurons
      - Large-diameter mechanoreceptors
      - Unmyelinated small-diameter peptidergic nociceptors
    - Sensory nerve terminals
      - Meissner corpuscles lanceolate fibers
      - Rapidly adapting low-threshold mechanoreceptors
    - Free nerve endings: ? Nociceptors
  - Low pH opens channel to Na⁺ & Ca⁺⁺
  - Curent: Biphasic; Rapidly inactivating & Sustained components
  - Inhibitor: Amiloride
  - Functions: Related to
    - Stimuli: Cutaneous touch; Acid
    - Role for ASIC3 in tonic inhibition of high-intensity pain signals
  - Increased activity in: Obese mice 2° high lipid diet
  - ASIC3-deficient mouse
    - Reduced sensitivity of some mechanoreceptors to noxious pinch
    - Enhanced sensitivity to light touch
    - Enhanced behavioral responses to high-intensity nociceptive stimuli
- ACCN4 (ASIC-4) (SPASIC)
  - Expressed in pituitary & brain
- ASIC-5 (hINaC (human intestine Na⁺ channel))
  - Brain: Vestibulocerebellum granular layer metabotropic glutamate receptor-1 alpha-positive unipolar brush cells
- Capsaicin receptor (VR1)

Na-K-Cl CO-TRANSPORTERS (Solute carrier family (SLC) 12)

General
- Integral membrane proteins
- Mediate coupled transport of Na⁺, K⁺, & Cl^- across plasma membrane
- KCC family members: Potassium-Chloride cotransporters
Types
- SLC12A1 : Renal
  - Mediates active reabsorption of NaCl
  - Location: Thick ascending limb of the loop of Henle
  - Site of action of diuretics: Furosemide; Bumetanide
  - Disease: Bartter syndrome (Antenatal)
- SLC12A2
  - Expressed in many tissues: Secretory epithelia
  - Mediates active Cl^- secretion
  - Mouse mutation
    - Deafness; Shaker/waltzer behavior, indicative of inner-ear defects
    - Endolymph secretion: Reduced
- SLC12A3 : Renal
  - Distal convoluted tubule: Principal mediator of Na⁺ & Cl^- in this segment
  - Target of thiazide diuretics
  - Disease: Bartter syndrome (Gitelman variant)
- SLC12A4 (KCC1) : Early erythroid maturation
- SLC12A5 (KCC2)
  - Chloride extruder in brain
  - Promotes fast hyperpolarizing postsynaptic inhibition
  - Expressed in: Dorsal horn neurons; Not primary afferents
  - KCC2 blockade: May be associated with tactile allodynia
  - Disorders
    - Epileptic encephalopathy, early infantile, 34 (EIEE34)
    - Knockout mouse: Early death; Abnormal axon spontaneous activity
- SLC12A6 (KCC3)
  - Tissues: Vascular endothelial; Brain; Heart; Skeletal muscle; Kidney
  - Increased activity with cell swelling
  - Disease: Andermann syndrome (HMSN & Agenesis of Corpus Callosum)
- SLC12A7 (KCC4) :
  - Highest expression in kidney, heart, lung, and liver
  - Knockout mice
    - Deafness: Outer hair cells of basal turns of the cochlea lost
    - Renal tubular acidosis: Other causes are hydrogen ATPase & AE1 (SLC4A1) anion exchanger
  - Function: Potassium recycling into Deiters cells after exit from hair cells

Stretch-activated non-selective cation channels (SA channels)

Mechanism: Mechanically-gated channels
Locations
- Ear
- Muscle spindles
- Vascular endothelial cells
- Neurosensory epithelia
Types

TRANSIENT RECEPTOR POTENTIAL (TRP) ION CHANNELS

General Features

Structure
- Subunits: Contain 6 membrane spanning domains
- Similarity
  - Voltage gated K+ (K_v)
  - Cyclic nucleotide gated (HCN & CNG)
  - Polycystic kidney disease proteins
- Form tetramers
- Pore lined by transmembrane domains 5 & 6
Location: Plasma membrane
Functions
- Cation channel, Non-selective
- Actions
  - Shift membrane potential to 0 mV
  - Depolarization from resting membrane potentials
  - Allow Ca⁺⁺ influx in non-excitable cells
- Some are temperature sensitive
- Sensations
  - TRPA1: Noxious cold receptor
  - TRPM8: Innocuous cold sensor
  - TRPV1: Noxious heat
  - TRPV4: Pain
  - Other pain related: TRPM2, TRPV3, TRPC3, TRPC4, TRPC5
  - Itch related
    - Nerve: TRPA1; TRPC3; TRPV1; TRPM8 (Inhibitory)
    - Keratinocytes (Skin): TRPV3; TRPV4
Channel opening: Linked to activation of 2nd messenger systems
- Activation of phospholipase C
- Generation of Inositol-1,4,5-triphosphate (Ins(1,4,5)P₃)
- Opening of Ins(1,4,5)P₃ receptor
- Response to depletion of intracellular calcium pools (Capacitative calcium entry)
Some TRP play a role in phototransduction

TRP families ¹²

Group 1
TRPC (canonical)
TRPV (vanilloid)
TRPM (melastatin)
TRPA (ankyrin)
TRPN (NOMPC-like)
Group 2
TRPP (polycystin)
TRPML (mucolipin)

TRPA receptors
- TRPA1 (ANKTM1) ²⁶
  - Stimuli: Pain-related
    - Thermal stimulus: < 17 °C; Noxious cold
    - Mechanoreceptors in hair cells
    - Chemical: Irritants
      - General: Activated by reactive chemicals that form covalent adducts with free cysteines and lysines in proteins
      - Stimuli: Formaldehyde; 4-Hydroxynonenal; Cinnamaldehyde; Mustard oil; Iodoacetamide
  - Pharmacologic stimulus effects: May evoke burning sensation
    - Icilin
    - Pungent natural agonist compounds in
      - Cinnamon oil (cinnamaldehyde)
      - Wintergreeen oil (methyl salicylate)
      - Clove oil (eugenol)
      - Mustard oil (allyl isothyocianate)
      - Ginger (gingerol)
      - Garlic (alllicin)
      - Wasabi (allyl isothiocyanate)
      - 4-Hydroxynonenal
    - Positive regulation: Bradykinin
  - Cell localization
    - Dorsal root ganglia
      - TRPA1 expressed in some cells that also express TRPV1 (heat-gated channel)
      - May be up-regulated by NGF via p38 MAPK pathway
    - Hair cells
  - Properties
    - Channel properties: Non-selective cation currents
    - Cold-activated channel: < 17 °C; Noxious
    - Location: Nociceptive cold-sensitive sensory neurons
      - Coexpressed with the capsaicin/heat receptor
      - Sensory neurons respond to capsaicin but not to menthol
  - Roles in
    - Nociceptivve pain
    - Inflammatory pain
    - Inherent episodic pain syndrome
    - Itch
  - Disease: Familial Episodic Pain Syndrome
  - TRPA1-deficient mice: Reduced response to chemical-induced tissue injury
TRPC receptors (STrpC)
- TRPC1 : Expression widespread; Activated by diacylglycerol (DAG) & Intracellular Ca⁺⁺ depletion
- TRPC2 : Vomeronasal organ, Testes, Heart, Brain, Sperm; ? Pseudogene in humans
- TRPC3 : Brain, Placenta, Heart, Muscle; Activated by DAG & InsP₃R; Inward & Outward rectifying
  - Participates in skeletal muscle contraction
  - Interacts with ryanodine receptor-1 (RyR1)
  - Disorders
    - Target of autoantibodies in myasthenia gravis: Especially with thymoma
    - SCA41
- TRPC4 : Brain cortex, Testes, Placenta, Adrenal, Endothelium; Receptor operated
- TRPC5 : Brain; Receptor operated
- TRPC6
  - Tissues: Lung, Brain, Muscle (Smooth)
  - Activated by DAG
  - Inward & Outward rectifying
  - Interacts with podocin & nephrin
  - Disease: Focal segmental glomerulosclerosis
- TRPC7 : Lung, Brain, Muscle (Smooth), Heart, Eye; Activated by DAG; Inward & Outward rectifying
TRPV receptors
- General: TRPV family contains many heat-sensitive channels
- TRPV1: Vanilloid receptor (VR1); Capsaicin receptor
  - Location
    - Brain
    - Spinal cord: Laminae II & III of dorsal horn
    - Peripheral sensory neurons
      - Location: DRG; Trigeminal; Nodose
      - Size: Small to medium diameter
      - Peptide & Non-peptide releasing
    - Other
      - Urinary bladder epithelium
      - Smooth muscle
      - Epidermal keratinocytes
      - Colon: Low-firing frequency (LF) cells
  - Subcellular location: Plasma membrane
  - Physiology
    - Outwardly rectifying
    - Cation channel: Relatively selective for Ca⁺⁺
  - Activated by
    - Capsaicin: Sensory ganglion cells & axons
    - Resiniferatoxin (RTX): Highly potent analog
    - Anandamide
      - Cannabinoid receptor ligand
      - Sensitized to anandamide by protein kinase C
    - Allicin
    - LPA
    - Double knot toxin (DkTx)
      - Traps TRPV1 pore in open state
      - Irreversible ligand
      - Bivalent molecule
      - Source: Tarantula
    - Temperature
      - Heat to noxious range: 43 °C to 45 °C (Lower after sensitization)
      - Steep temperature dependance
    - Low pH (Acid)
      - 2 effects of protons
        
        Activation of VR1 at room temperature: With extracellular pH < 6
        
        Currents resemble sustained component of proton-evoked responses in sensory neurons
        
        Potentiate responses of VR1 to capsaicin or heat
        
        Concentration range (pH 6–8) matches local acidosis associated with tissue injury
      - More mediation of sustained than transient responses
    - Mustard oil
  - Inhibitors
    - Capsazepine
    - Ruthenium red
    - Phosphatidylinositol (4,5)-bisphosphate
  - Release of VR1 from inhibitory control: Bradykinin & Nerve growth factor
  - Functions
    - Nociception
      - Heat, Acid or Stretch induced
      - Activation effects
        
        Releases neuropeptides (substance P) from nerve terminals
        
        Causes burning pain
      - Required for development of inflammatory hyperalgesia
    - Itch
    - Inflammation
    - Hypothermia
    - Integrates effects of noxious heat, low pH & vanilloid ligands on sensory neurons
  - Roles in
    - Neuropathic pain
    - Inflammatory pain
    - Visceral pain
  - Positive regulation: PKA; PKC; NGF
  - Associated molecules on neurons
    - NGF receptor (trkA)
    - GFRα3: Receptor for artemin
    - TRPA1
  - Experimental modification
    - VR1 knockout mouse
      - Severely deficient in moderate heat-evoked responses
      - Few heat-sensitive C axons
      - Reduced pain behavior at high temperatures (> 50°C)
      - No increased sensitivity to heat after tissue injury
    - Anti-VR1 serum: Ameliorates thermal allodynia and hyperalgesia in diabetic mice
- TRPV2 : Vanilloid receptor-related (VRL-1)
  - Location: Brain; Spinal cord; Spleen; Lung; Peripheral sensory neurons
  - Physiology
    - Outwardly rectifying
    - Ions: Ca⁺⁺ > Na⁺ permeability
    - Inhibition by ruthenium red
  - Noxious heat sensation: Activated at 53 °C
- TRPV3 (VRL-3)
  - Location: Keratinocytes
  - Activation
    - Warm temperatures (25 to 40 °C
    - High response at noxious hot temperatures
  - Role in
    - Hair morphogenesis
    - Thermosensation
  - Required for Epidermal growth factor receptor (EGFR) signaling in skin
- TRPV4 (VROAC; VRL-2) ³⁹
  - Location
    - Organs: Brain; Liver; Kidney; Fat; Heart; Skeletal muscle; Testes; Salivary gland; Trachea
    - Common cell type: Ciliated epithelial
    - Endothelium: 2 microdomains
      - Myoendothelial projections
      - Homocellular endothelial junctions
  - Channel
    - Cation channel
      - Ca⁺⁺ permeable
      - Nonselective
    - Outward rectifying
    - Mediates calcium influx
    - Mitochondria ⁴¹
      - Present in subpopulation of mitochondria
      - Ca⁺⁺ importer
      - Regulates Mitochondrial
        
        Numbers
        
        Ca⁺⁺-levels
        
        Temperature
  - Activation
    - Reduced osmolarity (Tonicity)
    - Mechanosensitive: ? via 2nd messenger
    - Thermosensitive: Warm (Physiologic) temperatures (25°C�40°C)
    - Lipid metabolites
      - 4α-phorbol 12,13-didecanoate (4αPDD)
      - Arachidonic acid
    - UVB
    - Signaling: PAR-2; IL17-R; Endothelin-R
    - Endogenous agonists: Pro-pain prostanoid (5,6-EET; PGE2)
    - Cell swelling
    - TRPV antagonist: Ruthenium red
    - Second messenger activating systems: PKC; PLC; PI3K
  - TRPV4 functions
    - Osmotic
      - Regulates: AQP5 abundance in hypotonic conditions
      - Mechano- and osmosensory functions in: Endothelia, Alveola of lung & Intestine
      - Mediates sensitivity of nociceptive dorsal root ganglion neurons to hypo-osmotic challenges
    - Mechanical hyperalgesia (Delayed onset muscle soreness (DOMS))
    - Endothelium-dependent hyperpolarizations (EDH) ²⁹
      - Intracellular Ca⁺⁺ increase in endothelial cells via TRPV4
      - Leads to opening of Ca⁺⁺-activated K⁺ channels
        
        Small conductance [K_Ca2.3]
        
        Intermediate conductance [K_Ca3.1]
      - TRPV4 activation leads to: Smooth muscle cell hyperpolarization & Vasodilation
    - LPS-stimulated macrophage phagocytosis
    - Gastrointestinal: Activation reduces motility
    - Immune activation ⁴⁰
  - Auxiliary proteins
    - OS-9
    - WNK4
    - AQP5
    - AIP4 ubiquitin ligase
  - TRPV4 Diseases & Disorders ³⁸
    - Mutations: Often "Gain of function"
    - Neuropathic
      - General: Intra- & Inter-familial variability
      - HMSN 2C (CMT 2C)
      - Distal SMA, Congenital (HMN8): Spinal muscular atrophy, Congenital, non-progressive, of lower limbs
      - Scapuloperoneal SMA (SPSMA)
      - Itch: Serotonin-evoked
      - TRPV4: Roles in pain
        
        Mechanically evoked
        
        Inflammatory
        
        Neuropathic
        
        Visceral
        
        Trigeminal
    - Skeletal
      - General: Most with Short stature; Vertebral Δ, progressive
      - Metatropic Dysplasia (Metatropic Dwarfism) : Most severe
      - Brachyolmia type 3, Dominant (BCYM3)
      - Spondylometaphyseal Dysplasia, Kozlowski Type (SMDK)
      - Parastremmatic dwarfism
      - Spondyloepiphyseal Dysplasia, Maroteaux type
      - Familial Digital Arthropathy-Brachydactyly (FDAB): Least severe
    - Hearing loss: Sensorineural
    - TRPV4-null mice
      - Reduced sensitivity of tail to pressure & acidic nociception
- TRPV5 : ECAC-1
  - Location: Intestine; Kidney; Placenta
  - Inward rectification
  - Ca⁺⁺ selective
  - Conductance increases in absence of divalent catiions
  - Associated with 1,25 dihydroxyvitamin D3-dependent calbindin-D_28K
  - ? Role in Vitamin D responsive Ca⁺⁺ uptake
- TRPV6 : ECAC-2
  - Location: Widespread
  - Ca⁺⁺ selective
  - Inward rectification
  - Passes most current at hyperpolarized potentials
  - Activated by Ins(1,4,5)P₃ & thapsigargin-mediated store depletion
TRPM (Long TRP, Melastatin)
- TRPM1
  - Eye (Melanocytes)
  - Down-regulation prognostic marker for metastasis
- TRPM2
  - Brain (Fetal & Adult), Placenta
  - ADP-ribose regulation
  - Non-selective channel
- TRPM3
- TRPM4
  - Highest levels: Heart; Prostate; Colon; Kidney (In fetus)
  - Activated by intracellular Ca⁺⁺
  - Conducts monovalent cations: Na⁺ & K⁺
  - Modulates membrane potential
  - Diseases
    - Progressive familial heart block, type IB (PFHB1B)
    - Erythrokeratodermia veriabilis et progressiva 6 (EKPV6)
- TRPM5
  - Strong outward rectification
  - Nonselective among monovalent cations
  - Not permeable to divalent cations
  - Regulated by
    - Intracellular Ca⁺⁺: Activates & Desensitizes
    - PIP2: Reverses desensitization
  - Widely expressed
  - Taste transduction channel
  - Associated with Beckwith-Wiedemann syndrome
- TRPM6
  - Disease: Hypomagnesemia, intestinal with secondary hypocalcemia (HOMG1; HSH)
- TRPM7 (TRP-PLIK)
  - Kidney, Heart, Liver, Spleen, Lung, Brain
  - Regulated by activity of carboxy terminal kinase
  - Non-selective, whole cell current
  - Dual-function protein
    - Ion-channel domain fused to a serine-threonine α-kinase domain
    - Annexin I is substrate for TRPM7 kinase
  - Localized to synaptic vesicles
    - Required for release of acetylcholine
    - Reduced TRPM7 reduces quantal size
  - Disorders
    - May be associated with anoxic cell death
    - Mutations in some ALS-Guam patients
- TRPM8
  - Voltage-dependent gating cold-sensitive channel
    - Activation
      - Initial activation: Cooling to 28 °C
      - Activity increases as temperature diminishes: Increased probability of channel opening
      - Saturation: 10 °C
    - Agonists
      - Menthol receptor on axons
      - May also be activated by: Icilin, eucalyptol & WS-3
    - Positive regulation: Artemin; NFG
  - Channel properties: Nonselective outwardly rectifying channel
  - Mucosa axon distribution: Sub-epithelium; Profuse around blood vessels in deeper regions
  - Prostate, especially neoplasms
  - Upregulated by NGF
  - Roles in
    - Cold Allodynia (Cold hypersensitivity)
    - Neuropathic pain
TRPN & Other
- General features
  - Contain ankyrin repeats in N-terminals
- Painless
  - Stimulus: Heating (Noxious) to > 41°C
  - Present in multidendritic neurons: CNS & PNS
- no-mechanoreceptor-potential C (nompC)
  - Stimulus: Mechanical (Hair)
- Pyrexia
  - Gene encodes 2 proteins: PYX-PA & PYX-PB
  - Sequence homologies to other TRP proteins: ANKTM1; Painless
  - Subunits form heteromeric channels
  - Expressed along dendrites of a subset of peripheral nervous system neurons
  - Opened by temperatures above 40 °C
  - More permeable to K⁺ than to Na⁺
  - Protects against high temperature stress
TRPP: PKD (Polycystin) family
- PKD Function
  - PKD1 & PKD 2 interact to produce Ca⁺⁺-permeable nonselective cation currents
  - Ion channel: Contributes to fluid-flow sensation by primary cilium in renal epithelium
    - Activated by bending of the apical cilium in some epithelia
    - Senses fluid flow parallel to the epithelial surface.
- PKD1 (Polycystin 1) : Polycystic kidney disease, Dominant
- PKD2 (Polycystin 2; TRPP2)
  - Functions
    - Development: Cardiac, skeletal & renal development
    - Vessel wall integrity
    - Negative regulator of endogenous mechano-sensitive channels
    - Mechano-receptor & flow-sensor in endothelium
    - Apoptosis
  - Disorder: Polycystic kidney disease, Dominant
- TRPP3 (PK2L1)
  - Renal development
  - Sour sensor component
- TRPP5
  - Spermatogenesis
TRPML (Mucolipin)
- TRPML1 (Mucolipoin-1; MCOLN1)
  - Ubiquitous
  - Intracellular cation channel
  - Endo- lysosomal transmembrane Ca⁺⁺ channel
  - Functions
    - Endocytosis
    - Endosomal/lysosomal function
    - Autophagy regulation
    - ? Ca⁺⁺transport regulating lysosomal exocytosis
    - Control of membrane trafficking of proteins & lipids
  - Disease
    - Mucolipidosis IV
- TRPML2 (Mucolipin 2; MCOLN2)
  - Ubiquitous
  - Intracellular ion channel
  - Functions
    - Endosomal/lysosomal function
- TRPML3 (Mucolipin 3; MCOLN3)
  - Hair cells (stria vascularis, stereocilia)
  - Intracellular ion channel
  - Functions
    - Endosomal/lysosomal function
    - Autophagy
    - Hair cell maturation
  - Mouse disorder: varitint-waddler (Va) with tricolor & hearing loss

GAP JUNCTIONS ²³

Gap junction

External link: Expasy
General
- Definition: Clusters of intercellular channels connecting cytoplasms of two cells
- Functions: Coupling
  - Metabolic: Flow of metabolites between cells
  - Electrical: Flow of ions between cells
    - Signaling between neurons
    - Especially prominent in developing nervous system
    - May affect the dynamics of brain circuits: Synchronous firing of coupled neurons
  - Patterns
    - Symmetric
      - Non-rectifying
      - ± Voltage-sensitive
      - Behavior independent of hyperpolarized side
    - Asymmetric
      - May depend on: Type of channel; Properties of coupled cells
      - May be rectifying
- Formed by: Connexins (Vertebrates); Innexins (Invertebrates)
- Structure
  - Each intercellular channel of a cluster comprises one multimeric hemichannel from each cell
  - Each species contains a family of gap-junction monomers
  - Each cell usually expresses more than one type of monomer
Connexins
- General: Connexin properties & association with gap junctions
  - Multi-gene family
    - Number: 21 in humans
    - Sequence homology: 40%
  - Molecular structure of connexins
    - Membrane-spanning domains: Four; α-helical
    - Extracellular: 2 loops
    - Cytoplasmic: Carboxy and amino terminal sequences; 1 Loop
  - Connexon
    - Formed by a hexameric array of connexins
    - May be homomeric or heteromeric
  - Gap junction structure
    - Composition
      - Pair of connexons joined end-to-end in extracellular space: Forms tight seal
      - Connexons may be same (Homotypic) or different (Heterotypic)
    - Forms a hydrophilic intercellular membrane channel
    - Associated with 2 to 3 nm gap between neighboring cell membranes
  - Gap junction channel function
    - Allows diffusion of low molecular weight molecules (< 1kDa) between neighboring cells
    - Molecule types: Ions; Amino acids; Nucleotides; Cyclic AMP; Glucose-6-phosphate; Tetrahydrofolic acid
    - Gating: Controlled by multiple factors
      - Calcium concentration
        
        Closed by high concentrations: Mediated by calmodulin
      - pH: Closed at acid pH
      - Transjunctional membrane potential: Closed by large transjunctional voltages
      - Protein phosphorylation
  - Gap junctions: Associated structures
    - Cadherin-based adherens junctions
  - Disease syndromes caused by connexin mutations
    - Deafness
    - Polyneuropathy
    - Skin disorders
    - Cataracts
- Types of connexins
  - Connexin 26 (GJB2; CXB2)
    - Diseases
      - Non-syndromic deafness - Recessive & Dominant (DFNA3)
      - Vohwinkel syndrome
      - Heterozygosity: Exacerbating factor for A1555G mitochondrial deafness (Aminoglycoside)
  - Connexin 29 (GJC3; GJE1)
    - Locations
      - Tissues: Brain, Spinal cord, Peripheral nerve
      - Subcellular: Schwann cell membrane near Kv1.2 channels on axon
  - Connexin 30 (GJB6)
    - Diseases
      - Deafness, Autosomal dominant, Nonsyndromic Sensorineural 3 (DFNA3)
      - Ectodermal dysplasia 2, Hidrotic (Clouston syndrome) ²¹
        
        Clinical: Strabismus, Mental deficiency, Finger clubbing, Palmar hyperkeratosis
        
        Mutant protein
        
        Forms functional hemichannels at cell surface
        
        Generates leakage of ATP into extracellular space
  - Connexin 30.3 (GJB4)
    - Disease: Erythrokeratodermia variabilis
  - Connexin 31 (GJB3)
    - Diseases
      - Erythrokeratodermia variabilis
      - Bilateral high-frequency hearing loss (AD)
      - Hearing loss & polyneuropathy
  - Connexin 32 (GJB1; CXB1)
    - Disease: CMT-X
  - Connexin 36 (GJA9) : Formation of functional gap junctions in neocortex interneurons
  - Connexin 40 (GJA5)
    - Cardiac: Intercalated disk regions of left ventricle
    - Diseases
      - Atrial fibrillation 11
      - Atrial standstill, digenic
  - Connexin 43 (CXA1; GJA1)
    - Tissue: Heart; Endothelial cells
    - Diseases
      - Oculodentodigital dysplasia syndromes
        
        Dominant
        
        Recessive
        Syndactyly, type III
      - Atrioventricular septal defect 3
      - Craniometaphyseal dysplasia, autosomal recessive
        
        Cranial nerve compression: Hearing loss; VII palsy
      - Hypoplastic left heart syndrome 1
    - Mouse knockout: Cardiac right ventricular outflow obstruction
  - Connexin 46 (GJA3)
    - Disease
      - Cataract, Zonular Pulverulent, 3
      - Animal model: Nuclear cataracts with proteolysis of crystallins
  - Connexin 46.6 (GJC2; GJA12)
    - Diseases
      - Pelizaeus-Merzbacher-like syndrome
      - SPG44
      - Lymphedema, hereditary, IC
  - Connexin 50 (GJA8)
    - Diseases: Cataract, Zonular pulverulent 1
  - Other connexins
    - 25 (GJB7)
    - 30.2 (31.3; GJC3)
    - 31.1 (GJB5) : Skin
    - 31.9 (GJC1) : Gated by cytoplasmic acidification or halothane
    - 33 (GJA6) : Testis
    - 37 (GJA4) : Multiple organs
    - 40.1 (GJD4)
    - 45 (GJA7)
    - 59 (GJA9)
    - 62 (GJA10)
Other cell junctions involved in intercellular adhesion include
- Desmosomes
  - Large bundles: Anchor epithelial cells together
  - Proteins: Desmocollins; Desmogleins; Plakoglobins; Desmoplakins
  - Diseases: Pemphigus; Congenital muscular dystrophy; Naxos disease
- Tight junctions
  - Leave little space (< 1 nm) between two plasma membranes
  - Functions
    - Selectively modulate paracellular permeability between extracellular compartments
    - Act as boundary between apical & basolateral plasma membrane: Maintain epithelial cell polarity
  - Proteins: Cingulin; Zo-1, -2 & -3; Claudins; Occludin, JAM, Symplekin, 7H6 antigen
  - Diseases
    - Claudin-11 : In oligodendrocytes; Mouse knockout ? CNS myelin abnormalities
    - Claudin-14 : Deafness, Autosomal Recessive (DFNB29)
    - Claudin-16 : Primary Hypomagnesemia

ION CHANNEL-BINDING PROTEINS: INTRACELLULAR

Ion channel	Binding protein	Mechanism & Effect
K⁺ channel, Voltage-gated Shaker type NMDA receptor NR2 subunit	Chapsyns*: PSD-95 ; SAP97 ; Chapsyn-110 ; Sap102 ; Dlg	Binding via PDZ** domains 1st & 2nd on PSD-95 Post-synaptic densities in CNS
NMDA receptor NR1 subunit	α-actinin	Actin binding protein Concentrated in dendritic spines
Glycine receptor (GlyR)	Gephyrin	Binds to β intracellular loop of GlyR & tubulin
AChR: Nicotinic	Rapsyn/43K	Neuromuscular junction localization
Na⁺ channel Voltage-gated	Ankyrin G	Node of Ranvier localization
AMPA receptor GluR2 subunit	Glutamate receptor interacting protein (GRIP)	Binding via PDZ domain Couples receptor to cytoskeletal & signaling molecules
Glutamate receptor Metabotropic Subunits: mGluR1a & mGluR5	Homer	Binding via PDZ-like domain Expression ↑ by synaptic activity Cerebellar development

* Belong to Membrane Associated Guanylate Kinase (MAGUK) family
Chapsyn = Channel associated protein of synapse
** PDZ domains: Homologous 90 amino acid sequence repeats; Bind other proteins

Acetylcholine Receptors: Disorders

Muscle
- Myasthenia Gravis
  - Autoimmune: IgG vs α1 subunit
  - Hereditary
Neuronal
- Immune neuropathies
  - Syndromes
    - Autonomic, Subacute
    - Isaac's
    - Paraneoplastic syndrome: Some association with lung carcinoma
  - IgG antibody vs α3 subunit
- Epilepsy
  - Nocturnal frontal lobe, Type 1
    ● Neural nicotinic, α4 subunit ; Chromosome 20q13.2-q13.3; Dominant
  - Nocturnal frontal lobe, Type 3
    ● Neural nicotinic, β2 subunit (CHRNB2) ; Chromosome 1p21; Dominant
- Schizophrenia: Attention disorder
  - Lack of inhibition of P50 response to auditory stimulus
  - Linked to dinucleotide polymorphism at 15q13-q14: Site of α-7-nicotinic receptor
- Mouse knockouts
  - Lethal: e-AChR subunit loss
  - CNS neuronal loss with subunit knockout
    - Neural nicotinic, β2 subunit of AChR (CHRNB2)
      - Defects localized in CA1 and CA3 fields in hippocampus & neocortex
    - α7 subunit: Minimal phenotype
    - α9 subunit: Altered innervation of cochlear hair cells
  - Autonomic dysfunction
    - Knockouts of neural nicotinic AChR subunits
      - α3 : Bladder enlargement; Dilated, unresponsive pupils
      - β2
        
        Nicotine-elicited anti-nociception: Reduced
        
        Neurons in hippocampus & neocortex: Reduced
      - α4
        
        Nicotine-elicited anti-nociception: Reduced
Muscarinic
- IgG vs M₃-muscarinic AChRs: Occur in both 1° & 2° Sjögren's
Toxins
- Nicotinic agonists: Nicotine; Anatoxin A
- Nicotinic antagonists
  - Peptides: α-snake toxins; α-conotoxins
  - Other: d-tubocurarine; Histrionicotoxin; Lophotoxin; Epibatidine
- Muscarinic agonists: Muscarine; Arecoline; Pilocarpine; Green mamba snake
- Muscarinic antagonists: Scopolamine; Atropine

Glycine Receptors

Hyperekplexia (Startle disease)
● Glycine receptor α-1 subunit (strychnine binding) ; Chromosome 5q33-q35; Dominant or Recessive
- Same mutation in Spasmodic mouse
● β subunit ; Chromosome 4q31.3; Sporadic or Recessive
- Also: Spastic mouse
Toxins
- Picrotoxin: Non-competitive antagonist of glycine-activated Cl^- channel
- Strychnine: Competitive antagonist of glycine-gated Cl^- channel

Glutamate Receptors

Metabotropic glutamate receptor R1 (mGluR1): Paraneoplastic cerebellar degeneration
Metabotropic glutamate receptor R1 (mGluR3): Rasmussen's encephalitis

Long QT Syndromes ¹⁶

Cardiovascular disorder with tachyarrhythmias: Prolonged ventricular repolarization
- Ventricular fibrillation
- Torsade de pointes
  - Fibrillation with waxing and waning
  - Due to changing axis of depolarization
General: Molecular features
- Many LQT syndromes caused by K⁺ channel disorders
  - Some patients have digenic mutations
- Mechanisms: Current carried by defective K⁺ channels is impaired by
  - Reduced gating, or
  - Modified channel kinetics
- Non-K⁺ channels
Epidemiology
- Carriers: 1 in 10 000 persons
- Congenital long QT syndrome causes 3000 to 4000 sudden deaths in children & young adults per year in US
- Onset age: 50% by 12 years; 90% by 40 years
Clinical syndromes
- Autosomal-dominant (Romano–Ward syndrome): Pure cardiac phenotype
- Autosomal-recessive (Jervell and Lange–Nielsen syndrome): Association with congenital neuronal deafness
- Acquired long QT syndrome: Due to electrolyte disturbances or drug therapy
Risk factors for syncope or sudden cardiac death
- Congenital deafness
- History of syncope
- Female: Cardiac events more common generally & during pregnancy
- Males: Risk higher in childhood
- Documented torsade de pointes or ventricular fibrillation
- Age at first episode
- Duration of the corrected QT interval (QTc)
Clinical features
- Syncope
- Seizures
- Sudden death
- Treatment: β-blockers may reduce risk of cardiac events, especially LQT1
Dominant LQT syndromes
- LQT1 syndrome
  ● KCNQ1 (KVLQT voltage-gated K⁺ channel; KCNA8) ; Chromosome 11p15.5; Dominant or Recessive
  - Epidemiology
    - Prevalence: 42% of LQT syndromes
  - Genetics
    - KCNQ1 Disease syndromes
      - Long QT syndromes: Dominant or Recessive
      - Jervell & Lange-Nielsen Syndrome : Recessive
        
        Mutation suppresses dominant negative effect of truncated splice variant on full length isoform
        Heterzygotes: Some cardiac K⁺ current available for repolarization
      - Romano-Ward (LQT1) : Dominant
        
        Dominant negative effect of truncated splice variant on full length isoform
        No delayed rectifier K⁺ current
      - Atrial fibrillation, familial
      - Short QT syndrome 2
  - KCNQ1 protein: Disease mechanisms
    - Mutants often cause dominant negative effect on wild type channels
    - K⁺-selective outward (Repolarizing I_ks) current: Reduced
    - Prolongation of cardiac action potential: Produces predisposition to cardiac arrhythmias
  - Clinical
    - Cardiac
      - Stress-induced: Syncope; Palpitations; Torsade de pointe
      - Frequency of cardiac events with mutation: 63%
      - Risk of death from cardiac event: 4%
    - Congenital hearing loss
    - Onset: Earliest of common LQT syndromes
      - Males: Before puberty
      - Female: After puberty; Persisting cumulative risk
      - Median age: 9 years
    - Drugs provoking events
      - Mefloquine
      - Disopyramide
      - Terfenadine
      - Cisapride
    - Rx
      - Types: Opening K⁺ channels (Nicorandil); β-blockers
      - Not: Mexiletine
- LQT2
  ● HERG K⁺ channel (KCNH2; I_Kr) ; Chromosome 7q35-q36; Dominant-negative
  - Epidemiology
    - Prevalence: 45% of LQT syndromes
  - Genetics
    - Mutations: Several mechanisms of defect
      - Defect in biosynthetic processing
        
        HERG channel retained in the endoplasmic reticulum
      - No functional channels produced
      - HERG current with altered gating properties
    - Allelic disorder: SQT1
  - KCNH protein
    - Channel behavior: Inward rectifying
    - Normal function may suppress arrhythmias
  - Clinical
    - Onset: Median age 12 years
    - Cardiac clinical events
      - Precipitated by loud noise
      - Syncope, Aborted cardiac arrest, Sudden death
      - Frequency of cardiac events with mutation: 46%
      - Risk of death from cardiac event: 4%
    - Drugs provoking events
      - Clarithromycin
      - Quinidine
      - Sulfamethoxazole
      - Procainamide
      - Oxatomide
    - ? Rx by increasing serum K⁺
- LQT3
  ● Cardiac Na⁺ channel-α subunit; SCN5A ; Chromosome 3p21-p24; Dominant
  - Epidemiology
    - Prevalence: 8% of LQT syndromes
  - Genetics
    - Mutations also produce: Idiopathic ventricular fibrillation (Brugada syndrome )
  - SCN5A: Disease Mechanisms
    - Increased Na⁺ channel activity during plateau phase of the action potential
    - Leads to extra component of inward current: Prolongs repolarization
  - Clinical
    - Onset: Median age 16 years
    - Cardiac clinical events
      - Events occur at rest or during sleep
      - Syncope, Aborted cardiac arrest, Sudden death
      - Frequency of cardiac events with mutation: 18%
      - Risk of death from cardiac event: 20%
      - Cardiac events less frequent but more likely lethal than LQT1 or LQT2
    - Drugs provoking events: Halofantrine
    - Rx: Mexilletine; ? by Na channel blockade
- LQT4
  ● Ankyrin-B (ANK2) ; Chromosome 4q25-q26; Dominant
  - Genetics: Haploinsufficiency
  - ANK2: Disease mechanism: Defective targeting of calcium-handling proteins to transverse tubule membranes
    - Inositol 1,4,5-trisphosphate receptor
    - Sodium-calcium exchanger
    - Sodium-potassium ATPase (Na⁺/K⁺ ATPase)
  - Clinical
    - Sinus node dysfunction: Onset in utero
    - Bradycardia or Junctional escape rhythm
    - Episodes of atrial fibrillation
- LQT5
  ● KCNE1 (minK protein) ; Chromosome 21q22.1-q22.2; Dominant
  - Long QT
  - Jervell and Lange-Nielsen syndrome
- LQT6
  ● KCNE2 (minK related peptide 1) ; Chromosome 21q22.1; Dominant
  - Clinical syndromes
    - Long QT
    - Ventricular fibrillation
    - Clarithromycin-induced arrhythmia
- LQT7
  ● KCNJ2 ; Chromosome 17q23.1-q24.2; Dominant
  - Andersen cardiodysrhythmic periodic paralysis
- LQT8
  ● CACNA1C ; Chromosome 12p13.3; Dominant
  - Allelic disorders
    - Long QT syndrome with syndactyly (Timothy syndrome)
    - Brugada syndrome 3
- LQT9
  ● Caveolin-3 ; Chromosome 3q25; Dominant
  - Mutations: Heterozygous; Missense
  - Physiology: Increase in late sodium current of the cardiac sodium channel
  - Clinical syndromes
    - LQT
    - SIDS
- LQT10
  ● SCN4B ; Chromosome 11q23; Dominant
  - Mutation: Heterozygous; Missense
  - Clinical: Bradycardia; Long QT; Sudden death
- LQT11
  ● A-kinase anchor protein-9 (AKAP9) ; Chromosome 7q21-q22; Dominant
  - Mutation: Heterozygous; Missense
  - Clinical: Long QT
- LQT12
  ● α-1 syntrophin (SNTA1) ; Chromosome 20q11.2; Dominant
  - Mutation: Missense; A390V
  - Clinical: Long QT
- LQT13 Congenital syndrome
  ● KCNJ5 ; Chromosome 11q24; Dominant
  - Chinese family
  - Genetics
    - Mutation: Missense; Gly387Arg
    - Allelic with: Familial Hyperaldosteronism, Type 3
  - Clinical: Long QT
    - Syncope: With stress
    - Atrial: Tachycardia; Fibrillation
    - Atrioventricular block
- LQT14 syndrome
  ● CALM1 ; Chromosome 14q32.11; Dominant
  - Epidemiology: 2 families
  - Mutations: Missense
  - Clinical
    - Onset age: 1st or 2nd decade
    - Prolonged QT with exercise
- LQT15 syndrome
  ● Calmodulin-2 (CALM2) ; Chromosome 2p21; Dominant
  - Epidemiology: 6 patients
  - Mutations: Missense
  - Clinical
    - Onset age: Congenital
    - Bradycardia
    - Ventricular fibrillation
    - Sudden death
- LQT16 syndrome
  ● Calmodulin-3 (CALM3) ; Chromosome 19q13.32; Dominant or de novo
  - Epidemiology: 5 patients, 4 families
  - Genetics
    - Mutations: Missense
    - Allelic disorder: Catecholaminergic polymorphic ventricular tachycardia-6 (CPVT6)
  - CALM3 protein
    - Ca⁺⁺ binding
  - Clinical
    - Onset: Pernatal
    - Syncope
    - Cardiac arrest
    - Sudden death
  - Laboratory: EKG
    - Corrected QT (QTc) interval: Markedly prolonged
    - 2:1 atrioventricular (AV) block
    - Bradycardia
    - Ventricular tachyarrhythmias
Recessive LQT syndromes
- Long QT with congenital deafness (Jervell-Lange-Nielsen)
  ● K⁺ Voltage gated channel, ISK-related subfamily, Member 1 (KCNE1) ; Chromosome 21q22.1-q22.2; Recessive
  - Same phenotype as LQT1
  ● KCNQ1 (KCNA8; KVLQT1) ; Chromosome 11p15.5; Recessive
- Dilated Cardiomyopathy with Ataxia (DCMA)
  ● DNAJC19 (TIM14) ; Chromosome 3q26.33; Recessive
- Long-QT Syndrome & Pediatric Sudden Cardiac Arrest ²⁸
  ● Triadin (TRDN) ; Chromosome 6q22.31; Recessive
Long QT syndrome: Acquired
- HERG K⁺ channel blockade
- 2° Antiarrhythmic medications: Class IA or III

Short QT (SQT) Syndromes

SQT1
● KCNH2 ; Chromosome 7q36.1; Dominant
- Allelic disorder: LQT2
SQT2
● KCNQ1 ; Chromosome 11p15.5-p15.4; Dominant
- Allelic disorders
SQT3
● KCNJ2 ; Chromosome 17q24.3; Dominant
- Allelic disorders
SQT7
● SLC4A3 ; Chromosome 2q35; Dominant

Concepts in channelopathies

What are the properties of the mutations in the chloride channel gene (CLC1) that determine whether a syndrome is inherited in a dominant or recessive pattern?

The dominant or recessive nature of a mutation depends on the ability of the mutant chloride channel monomers to polymerize with normal channel monomers. Dominant mutations complex with normal monomers producing defective channels. For some mutations one abnormal monomer is sufficient to destroy the function of a tetramer complex (e.g. Pro480Leu). For other mutations (e.g. Gly230Glu) it requires two abnomal monomers to destroy the channel function of a tetramer. In either case, only a minority of tetramers remain functional and myotonia results. Recessive mutations do not complex with normal monomers. Normal monomers are then free to complex with other normal monomers. This produces enough functional tetramers in heterozygotes (50% of the usual amount) to preserve normal membrane excitablity and myotonia does not occur.

What are the properties of the mutations in the sodium channel gene (SCN4A) that determine whether a syndrome presents with myotonia, paramyotonia, or weakness?

Many mutations produce abnormal inactivation of the sodium channel. This results in increased sodium conductance and membrane depolarization. Mild depolarization is associated with increased membrane excitability and myotonia. Strong depolarization produces membrane inexcitability and weakness. Some mutations only reduce inactivation at low temperatures producing paramyotonic disorders (myotonia or weakness worse in the cold). Mutations in the inactivation gate (amino acid 1306) produce different degrees of disease severity depending on the size and charge of the side chain of the new amino acid. Alanine, with a short side chain produces mild myotonia fluctuans. Valine, with an intermediate side chain, produces paramyotonia congenita. Glutamic acid, with a long side chain and a negative charge, results in myotonia permanens.

Marine toxins: General ²⁴

Clinical
- Syndromes occur after ingestion of toxins
- Systems involved
  - Gastrointestinal
  - Neurological: Peripheral nerves
- Differs from painful cardiovascular effects of marine venom toxins
Toxin properties
- Heat and gastric-acid stable
- Low molecular-weight
- Affect voltage-gated Na+ channels: In myelinated & unmyelinated nerves

Ciguatera toxins ^7, ^8, ¹¹

Epidemiology
Toxicity
Clinical
Laboratory

Epidemiology: Marine toxin
- Geographic distribution
  - Caribbean
  - Indo-Pacific
  - Australia: Northeastern coast fish; Outbreaks in Sydney
- Incidence
  - 50,000 annually
  - Most common illness 2° finfish consumption
  - Occurs in small clusters of patients who shared one, or a few, large fish
  - Some Pacific & Caribbean island nations up to 10% incidence
- Patient characteristics
  - Males > Females
  - Age: 2nd & 3rd decade
  - Older individuals
    - Symptomatic first poisoning more common
    - Acute symptoms more severe
    - Duration of symptoms longer
- Food chain
  - Microalgae contaminated with Gamberdiscus: Benthic dinoflagellate on dead coral
  - Herbiverous fish consume contaminated microalgae
  - Carniverous fish eat contaminated herbivorous fish
  - Toxin is concentrated in all tissues of carnivorous fish: Especially liver & other viscera
  - Human ciguatera disease: Caused by ingestion of fish with high concentration of toxin
    - Toxic level: > 0.1 ppb (0.1 μg/kg)
    - Usually with ingestion of large fish: Rarely < 2 kg; Especially > 10 kg
    - Reef fish types
      - Barracuda (Sphyraena jello)
      - Ephanids: Flowery (Epinephelus fuscoguttatus) & Spotted cod
      - Moray eel (Lycodotis): Most toxic
      - Serranids: Coral trout (Plectropomus leopardus) from Great Barrier reef; Grouper; Sea bass
      - Lutjanids: Red bass & snapper
      - Amberjack
      - Scombrids: Spanish mackerel (Scomberomorus commersom) & tunas
      - Carangids: Jacks & Scads
      - Lethrinids: Emperors & Scavengers
      - Sea bass
      - Sturgeon
      - Surgeonfish
      - Parrotfish
      - Red snapper
Toxicity
- Ingestion: Contaminated predatory fish
- Toxin
  - Type: Neutral polyether, Lipophilic cyclic
  - Properties
    - Heat-stable
    - Lipid soluble: Long retention in neuronal lipid membranes
  - Dinoflagellate toxins (Gambierdiscus toxicus & polynesiensis)
    - Associated with
      - Dead coral
      - Blue-green algae
    - > 20 different gambier- & ciguatoxins
      - Ciguatoxins bind to site 5 (transmembrane segment) on α-subunit of Na⁺ channel
      - Most prolong Na⁺ channel opening
      - One blocks Na⁺ channels
    - Produced in precursor form by Gamberdiscus polynesiensis
    - Biotransformed to active more polar toxin in fish
    - Ciguatoxin types
      - Pacific
        
        > 20 types
        
        Pacific-ciguatoxin-1 (P-CTX-1)
        
        Percursors: CTX3B/C; CTX4A/B
        
        More: Toxic; Neurological
      - Caribbean
        
        12 types
        
        Caribbean-ciguatoxin-1 (C-CTX-1)
        
        More GI features
  - Mechanisms of action
    - Inactivation of voltage-gated Na⁺ channels
    - Decreases threshold for opening voltage-gated sodium channels
    - Increases nerve membrane excitability
    - P-CTX-1
      - TTX-sensitive Na⁺ channels open closer to normal resting membrane potential
      - TTX-resistant Na⁺ channels recover from inactivation more quickly
    - TRPV1 channels: May be activated by polycyclic ether toxins
Clinical
- General
  - Gastrointestinal: More common in Caribbean; Earliest onset (~12 hours)
  - PNS (Paresthesias): Indo-Pacific; Onset ~24 hours
  - CNS (Hallucinations): Indian Ocean
- Rapid onset: 4 to 16 hours after ingestion
  - GI: Vomiting; Diarrhea; Abdominal pain
    - May produce electrolyte disturbances or dehydration: Especially children
    - Course: Self limiting over < 36 hours
  - Cardiac
    - Vasomotor: Bradycardia; Hypotension
  - Discomfort: Myalgias; Cramping; Pruritis; Headache
- Longer term symptoms: Onset after 12 hours
  - Most common: Weakness; Joint & Muscle pain; Paresthesias
  - Sensory
    - Sensory loss
      - Temperature (80%)
      - Pin & Vibration (50%)
    - Paresthesias & Pruritis: Intense
      - Often presenting symptoms
      - Especially in extremities
      - Centrifugal spread from mouth & tongue
      - Duration: Days to Months
    - "Reversal" of hot & cold sensation
      - Cold objects produce uncomfortable burning
      - Warm: Fluids especially disturbing; Cold-sharp sensation
    - Feelings of loose teeth
    - Taste disturbance: Metallic
    - Pain: Limbs; Skin; Joints; Dental; Urethral
  - Muscle
    - Pain
    - Weakness
      - May be related to neural involvement or inflammatory myopathy
      - Diffuse
      - Dysphagia
    - Fatigue
  - Autonomic
    - Hypersalivation
    - Bradycardia
    - Laryngospasm
    - Hypotension
    - Pupils: Large or Small
  - CNS
    - Headache: May be presenting feature
    - Depression
    - Cerebellar: Often later onset (Up to 10 days); Ataxia; Tremor
    - Short term memory loss
    - Insomnia
    - Coma in severe cases
  - Death
    - Frequency
      - Mortality is region-specific: Up to 20% in occasional episodes
      - Pacific < 1% of patients
    - Due to: Shock; Respiratory failure
    - Occurs when more toxic parts of fish (liver, roe) ingested
  - Recovery
    - Time course: 6 to 24 months
    - Most persistent symptoms: Pruritis; Arthralgia; Fatigue
    - ? Toxin stored in adipose tissue
    - Exacerbations with: Alcohol ingestion; Stress; Exercise; Weight loss
- Chronic syndrome
  - Frequency: 3% to 20% of severe intoxications
  - Fatigability
  - Weakness
  - Depression
  - Hypersomnolence
- Subsequent attacks
  - Often more severe than 1st attack
  - Patients more sensitive to low doses of toxin
  - Avoid eating fish for 6 months after initial attack
- Pregnancy
  - ? Increased Fetal movements
  - Newborn after exposure: Normal or transient weakness
  - ? Breastfeeding may transmit toxin
- Treatment
  - Symptomatic: Analgesics; Antihistamines
  - Mannitol
    - Not supported by controlled study
    - In 1st 48 hours; 1g/kg over 1/2 to 4 hours; May be repeated 1 or 2 times
Laboratory
- Electrophysiology
  - Slow NCV & F-waves
  - Prolonged refractory periods
  - Repetitive axonal firing
  - Mild cases
    - Normal routine electrophysiology
    - Latent tetany: Multiplets persisting > 2 min after cessation of hyperventilation or ischemia
- Plasma cholinesterase: Reduced in 80%
- Diagnostic testing
  - Mouse bioassay: Injection of fish extracts
  - Immunoassay for Pacific-ciguatoxin -1
  - Confirmation by liquid chromatography/tandem mass spectrometry
- Pathology: Schwann cell cytoplasm edema
Differential diagnosis
- Clupeotoxism
- Other marine toxin syndromes
  - Tetrodotoxin
  - Shell fish intoxication: Saxitoxin; Gonyautoxin
  - Scombroid: 2° Histamine accumulation in spoiled fish

Clupeotoxism

From NCI

Palytoxin

Sources
- Plankton-eating fish: Sardines & Herring (Clupeoid fish)
- Hawaiian spear toxin
Probable producing organism: Ostreopsis siamensis (Benthic dinoflagellate)
Chemical class: Polyether
Active agent: Palytoxin
- Pore-forming toxin
- Converts Na⁺/K⁺ pumps into nonselective cation channels
- Increases H⁺ influx into cells: Increases intracellular Ca⁺⁺ in cardiac myocytes
- Causes depolarization, Na⁺ accumulation & Ca⁺⁺ overload
- Causes contraction of smooth & skeletal muscle
- May produce hemolysis
- Highly potent: Only botulinum & tetanus toxins active at lower concentrations
Clinical
- Produces a similar syndrome to ciguatera: May be mild or fatal
- Pain & Cramps: Muscle & Back
- Gastrointestinal: Nausea, Vomiting, Abdominal cramps & diarrhoea
- Sensory
  - Metallic taste
  - Paresthesias
- Weakness
- Pupils: Dilated
- CNS: Ataxia; Coma
- Mortality rate: High
Laboratory
- CK high
- Dark urine

Conotoxins

α: Bind to AChRs
- Muscle nicotinic: GI , GIA , GII , MI, SI , SIA , SII , EI
  - MI binds to α-γ subunit interface
  - EI binds to α-δ subunit interface > α-γ
- Neuronal
  - MII binds to α₃β₂
  - IMI binds to α₇
δ: Bind to Na⁺ channels
μ: Bind to Na⁺ channels
w: Bind to Ca⁺⁺ channels
- N-type: GVIA , MVIIA , SVIA
- N-, P- & Q-type: MVIIC , MVIID

Lidocaine

Blocks voltage-gated Na⁺ channels
Usage dependent
Requires open Na⁺ channels
Dosage effects
- Partial block: Slow NCV
- Higher dosage: Conduction block
- Very high dose: K⁺ channel block also

Saxitoxin

Toxicity
- Associated with "Red tides"
- Ingestion
  - Contaminated bivalve shellfish (mussels, oysters & clams)
  - Filter feeding of shell fish concentrates toxins
- Origin of toxin: Dinoflagellates (Gonyaulax toxin)
  - Alexandrium spp
  - Pyrodinium bahamense var compressum
  - Gymnodinium catenatum
  - Xanthid crab
  - External link
- Toxin type & properties
  - Guanidinium
  - Heterocyclic
  - Water soluble
  - Heat stable
- Mechanism of action
  - Binds to site 1 on voltage gated Na⁺ channel (Tetrodotoxin-sensitive channel)
  - Blocks Na⁺ flux
Clinical
- Onset
  - Rapid: 1/2 to 3 hous after ingestion
  - More rapid with increased severity of intoxication
- Paresthesias & Numbness
  - Early: Lips, tongue, extremities (distal)
  - May become generalized
- Weakness: Extremities, bulbar, respiratory
- Tendon reflexes: Preserved early
- CNS: Coma; Most patients alert
- Systemic: Cardiac arrhythmias
- Other
  - Headache
  - Nausea & vomiting
  - Hypersalivation & Diaphoresis
- Recovery: 2 to 7 days
- Death: Usually in first 12 hours
- External link: Epidemic report
Laboratory
- Electrophysiology
  - Slow NCV
  - Long distal latencies
  - Small motor & sensory action potentials
  - Conduction block
- Pathology: No morphologic changes
Diagnosis
- Mouse bioassay
- HPLC
Differential diagnosis: Similar clinical syndromes
- Tetrodotoxin
- Crab poisoning: External link
External link: Neil Edwards

Tetrodotoxin

Toxicity
- Ingestion: Improperly prepared fish
  - Species
    - Tetraodontiformes (Bony fish): Fugu rubripes (puffer) Sheroides rubripes (globe)
    - Other: Blue-ringed octopus bite
  - Concentrated in organs: Liver > Gonads (ovary) > Intestine > Skin
  - Usual patterns of ingestion
    - Served from October through March
    - Served with enough toxin: Causes tingling of lips
- Toxin
  - Type: Guanidinium; Heterocyclic
  - Water soluble
  - Produced by bacteria (Alteromas), not directly by fish
- Mechanism of action
  - Binds to site 1 on voltage gated Na⁺ channel: Occludes outer pore
    - Neutralization of negative amino acids 942 & 945 of S5-S6 loop reduces binding
    - Puffer fish have Na⁺ channel mutation: Reduced toxin binding to own channels
  - Blocks Na⁺ flux
    - Guanidinium moiety enters channel
    - Action independent of whether channel is open or closed
  - Physiology
    - Reduced action potential generation
    - Reduced propagation of action potentials
Tetrodotoxin
Clinical
- Onset
  - Rapid
  - 15 minutes to 12 hours after toxin ingestion
- Sensory
  - Numbness & paresthesia
    - Lips, tongue, extremities
  - Loss: ? Reduced proprioception
- Weakness
  - Extremities: Distal > Proximal
  - Bulbar & Facial
  - Respiratory
- Tendon reflexes: Preserved early
- CNS
  - Dizziness
  - Ataxia
  - Coma
- Autonomic: With more severe intoxication
  - Cardiac rhythm: Arrhythmias; Bradycardia
  - Hypotension
  - Pupils: Fixed, Dilated
- Consciousness: Normal
- Recovery: 4 to 5 days
Laboratory
- Diagnosis: Toxin detection in urine
- Electrophysiology
  - NCV: Slow
  - Long distal latencies
  - Conduction block
  - Small motor & sensory action potentials
  - High threshold for stimulation
- Pathology: No morphologic changes
Prognosis
- Mortality: High (50%)
- Good after survival for 24 hours
External link: Jim Johnson

Brevetoxins

From FDA

Epidemiology: Human poisoning reported in
- Florida: West coast
- North Carolina
- New Zealand
Organism in shell fish: Marine dinoflagellate Gymnodinium brevis
Chemistry
- Lipid-soluble polyether toxins
- Bind to voltage sensitive Na⁺ channels
  - Bind at site 5 on Na⁺ channels
  - Enhance Na⁺ entry into cells
  - Neuroexcitatory effect: Cause nerve-cell depolarization & spontaneous firing
Clinical
- Gastrointestinal effects: Abdominal pain, Nausea & Diarrhea
- Neurotoxic: Ciguatera-like
  - Paraesthesia
  - Temperature reversal
  - Myalgia
  - Vertigo
  - Ataxia
- Other
  - Rectal-burning & pain
  - Headache
  - Bradycardia
  - Mydriasis
- Severity: Usually mild
- Treatment: Supportive care

Domoic Acid

Epidemiology
- One human outbreak: Canada 1987; Mussels
- Mass deaths of marine mammals & sea birds
Biology
- Ingestion of contaminated organisms
- Produced by microscopic algae: Nitzschia
Chemistry
- Heat stable
- Water soluble
- Neuroexcitatory amino: Acts like glutamic acid
Clinical: Amnesic syndrome
- Gastrointestinal
  - Onset: 5 hours after exposure
  - Vomiting, abdominal cramps & diarrhea
  - More common in younger patients
- Toxic encephalopathy: Severe memory loss & confusion
  - Onset: 48 hours
  - Headache
  - Eye movements: Disordered
  - CNS excitability: Seizures; Myoclonus
  - Mental status disorders
    - Confusion & Disorientation
    - Short-term memory loss
    - Coma
- Systemic features
  - Hemodynamic instability
  - Cardiac arrhythmias
  - Respiratory secretions: Profuse
- Prognosis: Worse in older patients
- Pathology: Neuronal loss in amygdala and hippocampus

Diarrheic shellfish poisoning (DSP)

Caused by group of high molecular weight polyethers
Toxins
- Okadaic acid
- Dinophysis toxins
- Pectenotoxins
- Yessotoxin

Return to Myopathies
Return to Neuromuscular Syndromes
Return to Neuromuscular Home Page

References
1. TINS Supplement: June 1996, Handb Exp Pharmacol 2023 Jan 3
2. Toxin illustrations from Ion Channel Research
3. Neurology 1997;49:1196-1199
4. Curr Opin Neurobiol 1999;9:267-273
5. Trends in Neurosciences 1999;22:488-495
6. Am J Hum Genet 2000;66 (May)
7. Medical Jourmal of Australia 2000;172:176-179
8. Medical Jourmal of Australia 2000;172:160-162
9. Physiol Rev 2000;79:1317-1372; Clin Neurophysiol 2001;112:2-18
10. TINS 2000;23:393-398, Arch Neurol 2003;60:496-500
11. Muscle Nerve 2000;23:1598-1603; JNNP 2001;70:4-8
12. Nature Reviews:Neuroscience 2001;2:387-396
13. Arch Neurol 2001;58:1649-1653
14. Physiol Rev 2002;82:503-568
15. Nature 2002;417;501-502
16. Ann Intern Med 2002;137:981-992
17. Nature Neuroscience 2003;6;468-475
18. Physiological Reviews 2003;83:117-161
19. Ann Neurol 2003;54:239-243
20. Nature 2004;430:232-235
21. Hum Mol Genet 2004;13:1703�1714
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23. Molec Neurobiol 2004;30:341-357
24. Lancet Neurology 2005;4:219-228
25. Current Pharmaceutical Design 2005;11:1915-1940
26. J Neurosci 2007;27:11412-11415
27. Science 2011;333:1462-1466
28. Circulation 2015;131:2051-2060
29. J Cardiovasc Pharmacol 2015 Nov 26
30. Lancet 2018 Mar 28
31. Int J Mol Sci 2020;21(8)
32. Trends Neurosci 2018;41:442-456
33. Brain 2020;143:2421-2436
34. Elife 2019 Nov 1;8:e50403
35. Nature 2020 Oct;586(7829):457-462
36. Neurosci Lett. 2021 Nov 28
37. Curr Opin Nephrol Hypertens 2022;31:508-515
38. Eur J Paediatr Neurol 2021;32:46-55
39. Neurosci Lett 2022;770:136377
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41. Mitochondrion 2022 Oct 16
42. Biomolecules 2024;15:33

1/27/2025

ION CHANNELS, TRANSMITTERS, RECEPTORS & DISEASE

CHANNEL TYPES: General ⁹

CHLORIDE CHANNELS

SODIUM CHANNELS

CALCIUM CHANNELS

POTASSIUM CHANNELS

MAGNESIUM

ANION CHANNELS, EXCHANGERS & TRANSPORTERS

CATION CHANNELS

Cyclic Nucleotide-Gated

Cation Leak

PROTON-GATED ION CHANNELS: Neural

Na-K-Cl CO-TRANSPORTERS (Solute carrier family (SLC) 12)

Stretch-activated non-selective cation channels (SA channels)

TRANSIENT RECEPTOR POTENTIAL (TRP) ION CHANNELS

GAP JUNCTIONS ²³

ION CHANNEL-BINDING PROTEINS: INTRACELLULAR

Acetylcholine Receptors: Disorders

Glycine Receptors

Glutamate Receptors

Dopamine Receptors

Long QT Syndromes ¹⁶

Short QT (SQT) Syndromes

CHANNEL TOXINS

ION CHANNELS, TRANSMITTERS, RECEPTORS & DISEASE

CHANNEL TYPES: General 9

CHLORIDE CHANNELS

SODIUM CHANNELS

CALCIUM CHANNELS

POTASSIUM CHANNELS

MAGNESIUM

ANION CHANNELS, EXCHANGERS & TRANSPORTERS

CATION CHANNELS

Cyclic Nucleotide-Gated

Cation Leak

PROTON-GATED ION CHANNELS: Neural

Na-K-Cl CO-TRANSPORTERS (Solute carrier family (SLC) 12)

Stretch-activated non-selective cation channels (SA channels)

TRANSIENT RECEPTOR POTENTIAL (TRP) ION CHANNELS

GAP JUNCTIONS 23

ION CHANNEL-BINDING PROTEINS: INTRACELLULAR

Acetylcholine Receptors: Disorders

Glycine Receptors

Glutamate Receptors

Dopamine Receptors

Long QT Syndromes 16

Short QT (SQT) Syndromes

CHANNEL TOXINS

CHANNEL TYPES: General ⁹

GAP JUNCTIONS ²³

Long QT Syndromes ¹⁶