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.

Acetylcholine is the primary excitatory neurotransmitter in visceral smooth muscles, wherein it binds to and activates two muscarinic receptors subtypes, M and M, 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 Ca entry via L-type Ca channels and smooth muscle contraction. Studies of the muscarinic cation current in intestinal myocytes (mI) revealed its main molecular counterpart, receptor-operated TRPC4 channel, which is activated in synergy by both M and M receptors. M receptors activation is of permissive nature, while activation of M receptors via G proteins that are coupled to them plays a direct role in TRPC4 opening. Our understanding of signalling pathways underlying mI 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 M receptor and the M/M receptor complex elicits smooth muscle contraction, while at high agonist concentration M 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 gastrointestinal motility. This article is part of the Special Issue on "Ukrainian Neuroscience".