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ACETYLCHOLINE & ACETYLCHOLINE RECEPTORS (AChRs)

Acetylcholine (ACh) metabolism
Acetylcholine receptors (AChRs)
  Disorders
  Muscarinic AChRs
  Nicotinic AChRs
  Structure
  Venom binding
Autonomic function
Myasthenic Disorders


Acetylcholine
Precursors: Choline and acetyl-CoA
Synthesizing enzymes: Choline acetyl transferase
Metabolizing enzymes: Acetylcholinesterase
Metabolites: Choline and acetate

External link: Toledo


Acetylcholine receptors: Muscarinic
General
G protein-linked
7-transmembrane
Receptor subtypes Agonists Antagonists Second messenger Other
CHRM1 Methacholine MT-7 toxin
Telenzepine
Pirenzepine
PI; G-protein
CHRM2 Methacholine Triptramine
Himbacine
Methoctramine
AFDX116
G-protein:
  Modulates K+ channel
cAMP: Inhibition
CHRM3 Methacholine Darifenacin
HHSiD
pFHHSiD
PI
G-protein:
    Pertussis toxin-insensitive Gq
Activates phospholipase C
Locations: Iris pupil sphincter; Detrusor muscle
Disorders
Urinary Bladder malformation, Congenital
Prune belly-like syndrome
CHRM4 Methacholine MT-3 toxin
Tropicamide
PD102807
G-protein:
  Modulates K+ channel
cAMP: Inhibition
CHRM5 Methacholine . PI; G-protein



ACETYLCHOLINE RECEPTORS: Nicotinic
ACh Receptor type
  & Subunits
Components/
  Location
Binding site
Dimer
Agonists Antagonists Channel
Blockers
2nd
messenger
Muscle AChRs
(α-bungarotoxin sensitive)
All: α1 ; β1 ; δ
Adult: e
Immature: γ
Adult: α1 e α1 β1 δ
Postsynaptic
  NMJs
Fetal: α1 γ α1 β1 δ
Extrajunctional

α1/e
α1/δ


α1/γ
α1/δ
  α-bungarotoxin,
(+)tubocurarine
GallamineCations
PCa/PNa =
    0.2-1
Neuronal AChRs
(α-bungarotoxin sensitive)
α7 ; α8 (Chickens)
(α7)5 Homomeric
CNS & PNS;
Developing
  muscle
α7/α7 Anatoxin
Rapid agonist
 desensitization
α-bungarotoxin
Methyllycaconitine
Erabutoxin
  Cations
PCa/PNa =
    6-20
Neuronal & Autonomic
(α-bungarotoxin
    insensitive)
α: 2 ; 3 ; 4 ; 5
β: 2 ; 3 ; 4
α3 β4 α3β4 β4
α3 β2 α3β4 α5
Ganglion
α4 β2 α4β2 β2
Brain
High Nicotine
  affinity
α3/β4
α3/β2


α4/β2



Cytisine
Nicotine
ABT418
Epibatidine
κ-bungarotoxin
Hexamethonium
Mecamylamine
Dihydro-
  βerythroidine
Cations
PCa/PNa =
    0.5-6
Epithelial & Neuronal
(α-bungarotoxin sensitive)
α9
(α9)5 Homomeric
Cochlea
  hair cells
α9/α9 Rapid agonist
 desensitization
Strychnine
Atropine
  Cations
PCa/PNa =
    6-20

Muscle AChR
(Adult)
Nicotinic AChRs1
  • All nicotinic AChRs are pentamers
    • Subunits clustered around central receptor channel
    • Members of superfamily of ligand-gated ion channels
      • Mediate fast signal transmission at synapses
    • Most AChR subunits have N-glycosylation site at amino acid 141
  • Domains
    • Extracellular
      • N-terminal: Contains disulfide linked loop
      • Main immunogenic region (MIR): Extracellular tip of α1 subunits
    • Transmembrane: Each subunit has 4 (M1 - M4)
      • M1-M3 α-helical
      • Ion channel lining: N-terminal third of M1 & One side of M2
    • Cytoplasmic: Most variable in sequence between subunits
  • ACh binding site
    • Dimer formed by
      • 3 or more peptide loops on α subunit (Principal component)
      • 2 loops on adjacent subunit (complementary component)
    • Activity
      • Binding to both sites needed for channel to open
      • Binding to only one site prevents channel activation
  • Subunits of AChRs
    • α Subunit
      • Defined by: Disulfide linked cysteine pair homologous to AA 192-193 of α1 subunit
      • AA 192-193: Region comprises one of 3 loops forming ACh binding site
      • Extracellular AA 66-76 of α1 contribute to Main immunogenic region (MIR)
      • Disorders
    • β Subunit
      • Component of agrin signalling pathway for AChR clustering
      • Phosphorylation of tyrosine 390 regulates cytoskeletal anchoring of AChRs
      • Disorders
    • δ Subunit
    • e Subunit
      • Location: Concentrated at adult NMJs
      • Half-Life: 10 days at innervated NMJs; 3 to 5 days at denervated NMJs
      • Physiology: Shorter open times & Higher conductance than γ-subunit containing AChRs
      • Disorders
    • γ Subunit
      • Location: Extrajunctional membrane in denervated muscle; Denervated NMJs
      • Half-Life: 1 day
      • Physiology: Longer open times & Lower conductance than e-subunit containing AChRs
      • Disorder
  • Antigenic epitopes
    • T-lymphocyte: Throughout AChR sequence
    • Anti-AChR antibodies: Main immunogenic region
  • Neuromuscular junction: AChRs
    • Subunits: α, β, δ, ε
    • Location: Terminal expansions of postsynaptic junctional folds
    • Density: ~10,000 AChRs/μm2
    • Channel properties: Cation-selective; Na+>Ca++
  • Neuronal AChRs: 2 Families
    • Heteromeric
      • Formed from combinations of: α2-α6 & β2-β4
      • Function: Often modulate release of other transmitters
      • No binding of α-bungarotoxin
      • High Ca++ permeability
    • Homomeric
      • α7 & α9 subunits
      • Distribution: Pre- & Post-synaptic neurons; Developing muscle
      • Bind α-bungarotoxin
    • Disorders
  • Also see




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Return to Molecular classifications
Return to AChR disorders

References
1. Muscle Nerve 2000;23:453-477

11/10/2011