Functions of Muscarinic Receptor Subtypes in Gastrointestinal Smooth Muscle: A Review of Studies with Receptor-Knockout Mice

Abstract

Parasympathetic signalling via muscarinic acetylcholine receptors (mAChRs) regulates gastrointestinal smooth muscle function. In most instances, the mAChR population in smooth muscle consists mainly of M2 and M3 subtypes in a roughly 80% to 20% mixture. Stimulation of these mAChRs triggers a complex array of biochemical and electrical events in the cell via associated G proteins, leading to smooth muscle contraction and facilitating gastrointestinal motility. Major signalling events induced by mAChRs include adenylyl cyclase inhibition, phosphoinositide hydrolysis, intracellular Ca2+ mobilisation, myofilament Ca2+ sensitisation, generation of non-selective cationic and chloride currents, K+ current modulation, inhibition or potentiation of voltage-dependent Ca2+ currents and membrane depolarisation. A lack of ligands with a high degree of receptor subtype selectivity and the frequent contribution of multiple receptor subtypes to responses in the same cell type have hampered studies on the signal transduction mechanisms and functions of individual mAChR subtypes. Therefore, novel strategies such as genetic manipulation are required to elucidate both the contributions of specific AChR subtypes to smooth muscle function and the underlying molecular mechanisms. In this article, we review recent studies on muscarinic function in gastrointestinal smooth muscle using mAChR subtype-knockout mice.

Potential Role for Combined Subtype-Selective Targeting of M1 and M3 Muscarinic Receptors in Gastrointestinal and Liver Diseases

“…GI motility, through intestinal smooth muscle cell action, involves communication between the central and enteric nervous systems. These effects are partially mediated by M 1 R through M 3 R ( Moro et al, 2005 ), with M 2 R and M 3 R playing a role in regulating longitudinal muscle contraction, and all three MR subtypes involved in circular muscle function ( Harrington et al, 2010 ; Tanahashi et al, 2021 ). MR-mediated regulation of smooth muscle function extends throughout the entire GI tract.…”

Myorelaxant and antispasmodic effect of an aqueous extract of <i>Artemisia campestris</i> L. via calcium channel blocking and anticholinergic pathways

“…M3 receptors couple preferentially to Gq/11 proteins which induce stimulation of phospholipase C (PLC) hydrolysis of phosphoinositides resulting in the formation of inositol 1,4,5-trisphosphate (InsP 3 ) and diacylglycerol (DAG). In turn, InsP 3 releases Ca 2+ from the sarcoplasmic reticulum and DAG activates protein kinase C (PKC), leading to the phosphorylation of various proteins ( 27 ). Carbachol is a cholinergic agonist, which is a structural analog of acetylcholine and is not degraded by acetylcholinesterase.…”

Antispasmodic Effect of Asperidine B, a Pyrrolidine Derivative, through Inhibition of L-Type Ca2+ Channel in Rat Ileal Smooth Muscle

“…An increase in intracellular Ca 2+ concentration activates Ca 2+ -calmodulin-dependent myosin light chain kinase (MLCK), resulting in a smooth muscle contraction [ 14 ]. Besides acetylcholine-induced smooth muscle contractions leading to gastrointestinal motility by activating muscarinic acetylcholine receptors (mAChRs), an increase in cytosolic Ca 2+ concentrations and the stimulation of non-selective cation channels in the plasma membrane contribute to membrane depolarization and produce an influx of Ca 2+ via voltage-gated Ca 2+ channels [ 15 , 16 ].…”

“…In intestinal smooth muscle, calcium mobilization contributes to the activation of cPLA2 and arachidonic acid (AA)-dependent stimulation of calcium influx [ 19 ]. Since acetylcholine-induced contractions depend on intracellular Ca 2+ mobilization via the inositol 1,4,5-triphosphate (IP 3 ) receptor on Ca 2+ stores [ 20 ] and Ca 2+ influx via L-type Ca 2+ channels [ 21 ] through non-selective cation channel stimulation [ 15 ]. Our results might presume asperidine B to be an anticholinergic agent associated with the muscarinic receptor through calcium influx via L-type Ca 2+ channels and/or the release of intracellular calcium.…”