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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: General9

  • Extracellular ligand-gated channels: Nicotinoid
    • 5 Homologous polypeptide subunits
    • Subunits have 4 membrane spanning regions
    • Ligands: Neurotransmitters
    • Specific receptors
      • Nicotinic AChR
      • GABAA & GABAC
      • Glycine
      • 5-HT3
      • Glutamate activated anionic channels
        • Types: NMDA; AMPA; Kainate
        • 4 Homologous subunits
  • 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

Classes
  Voltage gated (CLCN; CLCK)
  Intracellular (CLIC)
  Calcium activated (CLCA)
  Anion channels (SLC4)
  Na-K-Cl Cotransporters
Principles
Disorders

Chloride channels: Principles14
Chloride channels: Disorders

SODIUM CHANNELS

Figure
Principles: Na+ channels
  Exchangers
  Non-voltage-gated
  Voltage-gated
Subunits
  SCNA; SCNB; SCNN
  NAH exchangers: SLC9; SLC other
  Cation (CNG)
Na+ channel disorders

Sodium channels: Principles Sodium channels: Disorders

CALCIUM CHANNELS

Ca++ channel disorders
Ca++ channel: Figures
Types
  Voltage-gated Ca++ channels
    Classes
      L; N; P; Q; R; T
    Principles
    CACN: A; B; G
  Other
    Ligand gated (ATP2)
    Intracellular activation (RYR; IP3)
    Ca++ sensors
    Cation (CNG-gated)
    Other (NAADP; EDG1)

  l Voltage-gated Ca++ entry channels: Principles   l Other Ca++ channels   l Ca++ sensors   l Ca++ channel disorders

POTASSIUM CHANNELS

Figure
K+ channel disorders
Principles
  Structure
  Functions
    Voltage gated
    Inwardly rectifying
    KCa
  Subunits
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

l Principles & Types of K+ Channels l Disorders of K+ Channels

MAGNESIUM

Magnesium Hypomagnesemia

ANION CHANNELS, EXCHANGERS & TRANSPORTERS


CATION CHANNELS


Cyclic Nucleotide-Gated


Cation Leak

Sodium leak channel, nonselective (NALCN)

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

General Features TRP families12

GAP JUNCTIONS23

Gap junction

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

GLYCINE RECEPTORS


GLUTAMATE RECEPTORS


DOPAMINE RECEPTORS


Long QT Syndromes16




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.




CHANNEL TOXINS

Marine toxins
  Ciguatoxin
  Conotoxins
  Palytoxin (Clupeotoxism)
  Tetrodotoxin
  Shell fish
    Saxitoxin: Paralytic
    Domoic acid: Encephalopathic
    Brevetoxins: Neurotoxic
    Diarrheic
Other
  Lidocaine
  Potassium channel


Marine toxins: General24
Ciguatera toxins7,8,11

Epidemiology
Toxicity
Clinical
Laboratory

Clupeotoxism

From NCI
Palytoxin

Conotoxins
Lidocaine
Saxitoxin
Tetrodotoxin
Brevetoxins

From FDA

Domoic Acid
Diarrheic shellfish poisoning (DSP)

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References
1. TINS Supplement: June 1996
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;13:17031714
22. Molec Neurobiol 2004;30:279-305
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

4/9/2014