Ion Channel Diseases

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ION CHANNELS, TRANSMITTERS, RECEPTORS & DISEASE

Channels & disorders
Anions
ATPase
Calcium
Chloride
Concepts
Cyclic nucleotide-gated
Gap junctions
Long QT Syndromes
Magnesium
Mitochondrial solute carriers
Na⁺, K⁺, Cl^- Co-transporters
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: General⁹

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
Disorders

Chloride channels: Principles¹⁴

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
      - Ubiquitous
      - Cell volume regulation
      - Activated by hyperpolarization, cell swelling & acidic pH
      - Mutation disorders: Idiopathic generalized epilepsies
    - CLCN-3
      - Brain, Kidney (Type B intercalated cells), Skeletal muscle, Lung, Retina
      - Intracellular
      - Endosomes & Synaptic vesicles
      - Knockout: Degeneration of hippocampus & retina
    - CLCN-4
      - Muscle, Brain, Heart, Kidney, Retina
      - Vesicular channel
    - CLCN-5
      - Kidney (Type A intercalated cells)
      - Endosomal channel
      - Renal endocytosis
      - ? Cl^- reabsorption
    - CLCN-6
      - Ubiquitous
      - Intracellular
      - 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
    - 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
        
        Bartter syndrome types 3 & 4
- 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 : Skeletal muscle; Fetal liver
  - CLIC3 : Plasma membrane; Interacts with Erk7
  - CLIC4 : Brain, Heart, Placenta, Skeletal muscle
  - 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
  l 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

Figure
Principles: Na⁺ channels
Exchangers
Non-voltage-gated
Voltage-gated
Na⁺ channel disorders

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
  - Localization
    - Clustered at axon initial segments, nodes of Ranvier & Post-synaptic folds of NMJ
    - Ankyrin_G necessary for clustering
  - Structure: Often α β1β2 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
        
        High levels in brain
        Blockers: Tetrodotoxin; Saxitoxin
      - SCN2A1 (α2; II) : Na_v1.2
        
        Most abundant form in brain
        Peripheral nerve: Initial segment; Nodes of Ranvier
        Blockers: Tetrodotoxin; Saxitoxin
        Mutations: Seizure disorder
      - SCN2A2
        
        High levels in brain
      - SCN3A (α3; III) : Na_v1.3
        
        High levels in brain
        Blockers: Tetrodotoxin; Saxitoxin
        Downregulated by: NGF; GDNF
      - SCN4A (μ1) : Na_v1.4
        
        Muscle
        
        Sarcolemma: High levels
        
        NMJ: Concentrated at base of folded post-synaptic membrane
        
        Blockers
        
        Tetrodotoxin
        
        μ-conotoxins: GIIIA, GIIIB, GIIIC
        
        Diseases
        
        Hyperkalemic periodic paralysis
        
        Paramyotonia
        
        Myotonia
        
        Myasthenia
      - SCN5A : Na_v1.5
        
        Heart; Initial phase of upstroke on EKG
        Skeletal muscle: Denervated
        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
        Congenital sick sinus syndrome
        CMD 1E
      - SCN7A : Na_x
        
        Heart; Uterus; Skeletal muscle (Fetal & Denervated)
      - SCN8A (PN4) : Na_v1.6
        
        Brain & Spinal cord
        Primary channel at
        
        Nodes of Ranvier: Mature
        
        Axon: Initial segments
        
        Physiology
        
        Currents: Fast transient; Smaller persistent (Contribute to intrinsic burst activity)
        
        Upregulation: Might produce hyperexcitability
        
        Diseases: motor endplate disease (med) mouse; dmu mouse
      - SCN9A (PN1) : Na_v1.7
        
        Similar to rat PN1: Dorsal root ganglia; Neuroendocrine (Adrenal & Thyroid)
        Properties
        
        Tetrodotoxin (TTX) sensitive
        
        See: SCN9A
        
        Diseases
        
        Familial erythermalgia
        
        Congenital inability to experience pain
        
        Paroxysmal Extreme Pain Disorder
      - SCN10A (PN3; SNS) : Na_v1.8
        
        Depolarized activation potential
        Kinetics: Slow inactivation; Rapid repriming
        Tetrodotoxin resistant
        Location: Small sensory neurons in PNS
        Upregulated by: NGF; GDNF
        Clinical associations
        
        Pain sensitization
        
        Cold-induced pain
        
        Pain induced when skin is cold
        
        Null mice: Analgesia to noxious mechanical stimuli
      - SCN11A (NaN) : Na_v1.9
        
        Spinal sensory neurons: Dorsal root & Trigeminal ganglia
        Tetrodotoxin resistant
        Upregulated by: NGF; GDNF
        Channel openining (rapid) stimulated by BDNF via BDNF binding to TrkB receptor
        Clinical association: Pain sensitization
      - 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
      - Disease: Generalized epilepsy with febrile seizures +
    - 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
    - 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
    - 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
      - BNAC1 (ACCN1; ASIC2) : Cation channel; Abundant in brain neurons
      - BNAC2 (ACCN2; ASIC1) : Brain neurons
      - ACCN3 (DRASIC; ASIC3)
        
        Null mice: Enhanced responses to high-intensity painful stimuli
      - BNAC4 : Expressed in pituitary gland
- Sodium/Hydrogen exchangers
  - Function: Eliminate acids from intracellular space
  - Activation: Low intracellular pH
  - Inhibition: Amiloride
  - Types
    - NAH1 (SLC9A1)
      - Ubiquitous expression
      - Functions: Regulation of intracellular pH & cell volume
      - Mouse mutant
        
        Slow wave epilepsy (3 Hz); Ataxia
        Pathology: Cerebellum (Deep nuclei) & brainstem
    - NAH2 (SLC9A2)
      - Location: Intestine; Kidney
      - Function: Na⁺ ion absorption into mitochondria
    - NAH3 (SLC9A3) : Insensitive to amiloride
    - NAH4 (SLC9A4) : Stomach
    - NAH5 (SLC9A5) : Brain, Testis, Spleen, Skeletal muscle
    - SLC9A6 :
      - 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 :
      - 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
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)
- SLC24
  - Sodium/Potassium/Calcium exchanger (SLC24A1)
External link: UCLA anesthesia

Sodium channels: Disorders

Skeletal Muscle
- SCN4A, α-subunit
- 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 & nodes of Ranvier
- Hereditary
  - 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 : Fever associated seizures
  - Generalized epilepsy with febrile seizures plus, Type 2 (GEFS+2)
    - Mutations
      - Missense
      - Location: S4 & S5 transmembrane segments
      - Mutation action: Disrupts channel inactivation
    - Inheritance: Dominant
    - Clinical: Mild seizure disorder
  - Myoclonic Epilepsy of Infancy: Severe
    - Most mutations
      - De novo
      - Truncating type
      - Disease mechanism: ? Haploinsufficiency
    - Clinical: Ataxia; Severe seizures (Onset 2 to 6 months); Mental retardation
  - Infantile spasms
- α subunit: SCN2A1
  - Seizure disorders
    - Benign familial neonatal-infantile
    - Febrile & Afebrile
  - Seizure disorder in mice
    - Mutation action: Disrupts channel inactivation
- α subunit: SCN8A
  - Motor endplate disease (med) in mice
- β subunit: SCN1B
  - Generalized epilepsy with febrile seizures + (GEFS+1)
  - Mutation action: Disrupts channel inactivation
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
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 Toxins¹
- 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

l Voltage-gated Ca⁺⁺ entry channels: Principles

Ca⁺⁺ channels contain 4 or 5 distinct subunits
α-1 subunits
- Subtypes: Numerous; Different tissue & peptide specificity
  - α_1A (CACNA1A; P/Q type; Ca_v2.1) : Brain, Motor neurons, Kidney
  - α_1B (CACNA1B; N-type; Ca_v2.2) : CNS, PNS
  - α_1C (CACNA1C; L-type; Ca_v1.2) : Heart, Fibroblasts, Lung, Smooth muscle
  - α_1D (CACNA1D; L-type; Ca_v1.3) : Brain, Pancreas, Neuroendocrine
  - α_1E (CACNA1E; R-type; Ca_v2.3) : Brain, Muscle (NMJ)
  - α_1F (CACNA1F; Ca_v1.4) : Retina
  - 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
  - α_1S (CACNA1S; L-type; Ca_v1.1) : Skeletal muscle; L-type DHP receptor
- 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
Other subunits: Modulate channel functions
- α₂δ (CACNA2D)
  - 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 : Lung & Testis > Brain, Heart, Pancreas
  - 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
- γ (CACNG)
  - Cell location: Membrane spanning; No cytoplasmic domain
  - Size: 32kD
  - Subtypes
    - CACNG1 (γ) : 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
    - Mouse disorders
Ca⁺⁺ channel classes (Voltage-gated): Related to α-1 subunit
- L-type (Long lasting) Ca⁺⁺ channel
  - Subunits: α_1C, α_1D, α_1F, or α_1S, α₂δ, β_3a
  - Blockade
    - Sensitive to dihydropyridine (DHP) agonists and antagonists
    - Also blocked by phenylalkylamines (verapamil), benzothiazepines (diltiazem) & calciseptine
  - Activation: Strong depolarization
  - Inactivation by depolarization: Little
  - Localization
    - Skeletal muscle: α_1S
    - Brain (Neuronal soma & proximal dendrites): α_1D
    - Cardiac muscle: α_1C
    - 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: w-conotoxins GVIA (Strong; Irreversible) & MVIIA
  - DHP insensitive
  - Neuronal localization: Presynaptic
  - Constituents: No γ subunit; Novel 100 kd subunit
  - Modulation¹⁷
    - Enigma homolog (PKC binding protein) interacts with PKCe & N-type Ca⁺⁺ channels
    - Allows modulation of Ca⁺⁺ channel activity by PKCe
  - Function: Transmitter release from presynaptic nerve terminals
  - Diseases
- P-type Ca⁺⁺ channel
  - Subunits: α_1A, α₂δ, β_4a
  - Activation: Strong depolarization
  - Inactivation: Slow
  - Blockade: Funnel web spider venom; w-agatoxin IVA; w-conotoxin MVIIC
  - Insensitive to DHP & w-conotoxin GVIA
  - Localization
    - Neuronal presynaptic
    - High concentration of α_1A subunit in cerebellum: Purkinje cells
    - 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
  - Functions
    - Transmitter release
    - Insulin release: 2nd phase
  - Associated protein: EFHC1
    - Increases R-type Ca⁺⁺ channel currents
    - Mutations: Cause Juvenile myoclonic epilepsy
  - Location: Cerebellar granule neurons; Dendrites of hippocampal pyrimidal neurons
  - Action: Provide transient surge of Ca⁺⁺ influx
- T-type (Transient) Ca⁺⁺ channel¹⁸
  - Subunits
    - May be formed by single α₁ subunit
    - α_1G (Ca_v 3.1)
      - Localization: Brain
      - 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
    - α_1H (Ca_v 3.2)
      - Highest expression in kidney and liver; Also cardiac, neural, endocrine
      - Inhibition mediated by G protein β-2 , γ-2 subunits
      - Neural: D hair mechanoceptors; Sympathetic ganglion neurons
      - Skeletal muscle: Embryonic; Associated with myoblast fusion
      - Slowest recovery from inactivation
      - Currents generate short burst firing
      - Missense mutations associated with: Childhood Absence Epilepsy in Northern China
    - α_1I (Ca_v 3.3)
      - Brain specific
      - LVA currents: Activate and inactivate much more slowly than typical T-type channels
      - Currents contribute to sustained electrical activities in neurons
  - 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
    - Ethosuximide: Not at therapeutically relevant concentrations
    - Do not bind dihydropyridines
  - Tissue localization: Cardiac & vascular smooth muscle; Nervous system
  - Function
    - Rhythmic action (pacemaker) potentials in cardiac muscle & neurons
    - Burst firing 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

l 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
        
        Granulomatous myopathy: Antibodies vs RYR
        
        Myasthenia gravis: Antibodies vs RYR
    - 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, stress-induced polymorphic
    - RYR3 : Brain
- 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⁺⁺ channels⁵
- 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)

l 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

l Ca⁺⁺ channel disorders

L-type Ca⁺⁺ channel, voltage-gated; Skeletal muscle (CACNL1A3 α_1S) & other subunits
- Hypokalemic periodic paralysis (CACNL1A3 α_1S subunit)
- Malignant Hyperthermia
  - CACNL1A3 α_1S subunit
  - ? α2/δ subunit
- Long QT syndrome with syndactyly (Timothy syndrome): CACNA1C
- X-linked congenital stationary night blindness: Incomplete form (CSNB2)
  - Ca⁺⁺ channel, voltage-gated; α_1F subunit (CACNA1F) : Retina specific subunit
- 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)
P-type Ca⁺⁺ channel, voltage-gated; Presynaptic terminal of motor axon
- Lambert-Eaton Myasthenic Syndrome
- w-agatoxins: Especially IVA & IVB
- CACNA1A (CACNL1A4) 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
  - Progressive ataxia: SCA 6
    - Trinucleotide repeat expansion in intracellular region near carboxy terminus
    - Missense mutation: G293R
  - 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 epilepsy⁶
  - C104F: Generalized epilepsy & praxis-induced seizures; Episodic ataxia
R-type Ca⁺⁺ channel, voltage-gated; α_1E subunit
- ? Hemiplegic migraine
T-type Ca⁺⁺ channel, voltage-gated
- Greater current in reticular thalamic neurons in rat model of absence epilepsy
- Missense mutations of CACNA1H associated with: Childhood Absence Epilepsy in Northern China¹⁹
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

POTASSIUM CHANNELS

Figure
K⁺ channel disorders
Principles
Structure
Functions
Subunits
Types

l Principles & Types of K⁺ Channels

Structure⁴
- 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
K⁺ channel functions: Often voltage-sensitive
- 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
    - 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 the blockage of outward current by internal magnesium
    - Can be blocked by external Ba⁺⁺
    - Subcellular location: Integral membrane protein
    - Activity of Kir channels is 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
  - Human ether-a-go-go (HERG; KCNH) : Atypical with 6 transmembrane domains
  - See: Specific channel types; Disorders
- Ca⁺⁺ sensitive K⁺ channels: Generate membrane potential oscillations; Afterhyperpolarization
  - General structure & function¹⁵
    - 4 protein subunits
    - 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
  - High conductance (BK)
    - 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)
    - More sensitive to Ca⁺⁺ than BK channels
    - Gated only by internal Ca⁺⁺ ions
    - Unit conductance: 20 to 85 pS
    - Blockers: Cetiedil; Trifluoroperazine; Haloperidol
  - Small conductance (SK): 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
- ATP-sensitive K⁺ channels²⁵
  - General
    - Inhibitory effect: ATP
      - ATP acts from the cytoplasmic face of membrane
      - ATP reduces K⁺ channel open probability
    - Facilitation: Nucleoside diphosphate
  - Components
    - K+ pore: Kir6 subunits
      - KCNJ8
      - KCNJ11
    - 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
  - 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
- 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
- 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
        
        Form channels that are determinants of excitability of mammalian axons & nerve terminals
        
        KCNA 1, 5 & 6 genes located in cluster on Chromosome 12p13
      - KCNA1 (Kv1.1)
        
        Location
        
        Presynaptic & Juxtaparanodal membranes
        
        Present on dendrites
        
        Delayed rectifier
        
        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
      - 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
      - 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
      - External link: UCLA anesthesia
    - KCNB (Shab)
      - KCNB1 (Kv2.1)
        
        Locations: Soma; Proximal dendrite
        
        Associates with: KCNG3, KCNG4, KCNV2
      - 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) : Brain, Skeletal muscle, Lymphocytes, Spleen
      - 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
        
        Modulated by Neuronal calcium sensor 1
        Binds to Filamin C
      - KCND3 (Kv4.3) : Cardiac ventricle transient outward potassium current I(to)
    - 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
      - 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 one 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)
        
        Coexpressed with Kv2.1
        
        Physiology
        
        Accelerates time course of activation
        
        Hyperpolarizes threshold for activation
        
        Hyperpolarizes voltage dependence of inactivation
    - KCNQ family¹⁰
      - 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
        
        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
      - KCNQ2
        
        Locations
        
        Brain: Somatodendritic pyramidal & polymorphic neurons; Cortex & Hippocampus
        
        Sympathetic ganglia
        
        Testis
        
        Form M-channels with KCNQ3 & Calmodulin
        Diseases
        
        Benign neonatal epilepsy (EBN1)
        
        Myokymia & Benign neonatal epilepsy
      - KCNQ3
        
        Locations
        
        Brain: Somatodendritic pyramidal & polymorphic neurons; Cortex & Hippocampus
        
        Sympathetic ganglia
        
        Spleen
        
        Cochlea
        
        Form M-channels with KCNQ2 & 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
        
        Locations
        
        Brain
        
        Sympathetic ganglia
        
        Skeletal muscle
        
        Auxiliary subunit: KCNQ3
        M-current
    - 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: Cone dystrophy with supernormal rod electroretinogram
    - Brain cyclic nucleotide gated K⁺ channels (BCNG)²²
      - Types
        
        HCN1
        
        Expression in brain
        
        Activate rapidly
        
        Disruption: Impaired motor learning; Enhanced spatial learning & memory
        
        HCN2
        
        Expression: Brain & heart
        
        Deletion: Absence epilepsy, ataxia & sinus node dysfunction
        
        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
      - Properties
        
        Permeability
        
        Cations
        
        K⁺ 4x > Na⁺
        
        Current carried by Na⁺ ions at typical membrane voltages
        
        None to anions
        
        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: UCLA anesthesia
- 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
        
        Short QT syndrome 3
        Long QT syndrome 7
    - 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
      - Knockouts: Channel role in vagal regulation of heart rate & Spatial memory
    - KCNJ6 & KCNJ7 (Kir3.2)
      - Localization: Cerebellum
      - Associates with KCNJ9
      - Mediate inhibitory effects (outward currents) of opioids
      - Disorders: Weaver mouse
      - 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
        
        ? Related to glial K⁺ buffering in brain
        
        Endocochlear potentials
        K⁺ secretion
      - 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 : Unregulated insulin secretion
        
        May contribute to Type 2 diabetes: E23K polymorphism
        
        Neonatal diabetes, transient or permanent
        DEND: Developmental delay, Epilepsy & Neonatal Diabetes
        
        Treatment with sulfonylurea
    - 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
    - KCNJ14 (Kir2.4)
      - Cranial nerve motoneurons in general somatic & special visceral motor cell columns
    - KCNJ15 (Kir4.2)
      - Localization: Kidney
      - Forms heterodimer with KCNJ16
    - KCNJ16 (Kir5.1)
      - Tissues: Brain, Kidney & Pancreas
      - Functional channels formed with: KCNJ15; PSD-95
      - Associated with CO₂ chemoreception
    - KCNJN1
      - Inhibitor of KCNJ12 (Kir2.2)
  - Human ether-a-go-go (HERG; KCNH) : Related to cyclic nucleotide-gated cation channels
    - KCNH1
      - Expressed at onset of human myoblast differentiation
    - KCNH2
      - Channel activation accelerated by K⁺ Channel regulator 1
      - Diseases
        
        Long-QT 2 syndrome
        
        Short QT syndrome 1
    - KCNH3
      - 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
      - Locations: Brain specific
        
        Striatal regions: Putamen & caudate nucleus
        Lower levels in cerebral cortex & hippocampus
      - Electrophysiology
        
        Voltage-gated outward current
        
        No fast inactivation component
    - KCNH5
      - Adult brain tissue
    - KCNH6 (HERG2)
      - Time constant for deactivation: Voltage dependent; Decreased with more negative potentials
      - Deactivation kinetics slower than KCNH7
    - KCNH7 (HERG3)
      - 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 (TREK) :
    - Outward rectifying
    - Sensitive to extracellular K⁺ & Na⁺
    - Expressed in CNS
    - Activated by Halothane
  - KCNK3 (TASK)
    - Inhibited by extracellular acid: ? Role in cell response to extracellular pH
    - Activated by Halothane
  - KCNK4 (TRAAK)
    - Expressed in neural tissues
    - Cu

ION CHANNELS, TRANSMITTERS, RECEPTORS & DISEASE

CHANNEL TYPES: General9

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SODIUM CHANNELS

CALCIUM CHANNELS

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CHANNEL TYPES: General⁹