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ACETYLCHOLINE & ACETYLCHOLINE RECEPTORS (AChRs)

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

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: ε Immature: γ	Adult: α1 ε α1 β1 δ Postsynaptic   NMJs Fetal: α1 γ α1 β1 δ Extrajunctional	α1/ε α1/δ α1/γ α1/δ		α-bungarotoxin, (+)tubocurarine	Gallamine	Cations 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 AChRs 1 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): Includes ε or γ subunit Activity Binding to both sites needed for channel to open Binding to only one site prevents channel activation Fetal AChRs: 30x higher affinity for ACh 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 Disorders e Subunit Present in: Adult AChRs Location: Concentrated at adult NMJs Half-Life: 10 days at innervated NMJs; 3 to 5 days at denervated NMJs Physiology vs γ-subunit containing AChRs Shorter open times Higher conductance Disorders γ Subunit Present in: Fetal AChRs Location: Extrajunctional membrane in denervated muscle; Denervated NMJs Half-Life: 1 day Physiology vs e-subunit containing AChRs Longer open times Lower conductance ACh affinity: Higher 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 AChR disorders Also see AChR structure