Molecular mechanisms of cholinergic neurotransmission in visceral smooth muscles with a focus on receptor-operated TRPC4 channel and impairment of gastrointestinal motility by general anaesthetics and anxiolytics
NEUROPHARMACOLOGY(2024)
Abstract
Acetylcholine is the primary excitatory neurotransmitter in visceral smooth muscles, wherein it binds to and activates two muscarinic receptors subtypes, M2 and M3, thus causing smooth muscle excitation and contraction. The first part of this review focuses on the types of cells involved in cholinergic neurotransmission and on the molecular mechanisms underlying acetylcholine-induced membrane depolarisation, which is the central event of excitation-contraction coupling causing Ca2+ entry via L-type Ca2+ channels and smooth muscle contraction. Studies of the muscarinic cation current in intestinal myocytes (mICAT) revealed its main molecular counterpart, receptor-operated TRPC4 channel, which is activated in synergy by both M2 and M3 receptors. M3 receptors activation is of permissive nature, while activation of M2 receptors via Gi/o proteins that are coupled to them plays a direct role in TRPC4 opening. Our understanding of signalling pathways underlying mICAT generation has vastly expanded in recent years through studies of TRPC4 gating in native cells and its regulation in heterologous cells. Recent studies using muscarinic receptor knockout have established that at low agonist concentration activation of both M2 receptor and the M2/M3 receptor complex elicits smooth muscle contraction, while at high agonist concentration M3 receptor function becomes dominant. Based on this knowledge, in the second part of this review we discuss the cellular and molecular mechanisms underlying the numerous anticholinergic effects on neuroactive drugs, in particular general anaesthetics and anxiolytics, which can significantly impair gastro-intestinal motility.This article is part of the Special Issue on "Ukrainian Neuroscience".
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Key words
Gastrointestinal smooth muscle,Acetylcholine,Muscarinic receptor,TRPC4,General anaesthetics,Anxiolytics
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