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. 2021 Jan 18;22(2):926. doi: 10.3390/ijms22020926

Figure 1.

Figure 1

Three distinct muscarinic signalling pathways leading to transient receptor potential (TRP)-like cationic channel opening in ileal myocytes (redrawn from Tanahashi et al. 2020 [39]). The M3/Gq/11/phospholipase C (PLC) pathway activates brief opening states of 70-pS and 120-pS cationic channels and concurrently evokes InsP3-induced Ca2+ release. Opening of the lower conductance channel is induced by relief from PIP2 inhibition following PLC-mediated hydrolysis, while the higher conductance channel is activated by PLC-generated diacylglycerol (DAG). The M2 pathway transmits M2 signals via Gi/o proteins to the 70-pS channel, which shifts the gating state from the brief to a longer opening mode, and also inhibits adenylyl cyclase. The M2/M3 pathway transmits M2 signals via Go protein, and M3 signals via Gq/11/PLC, to the 70-pS cationic channel, resulting in channel gating with a much longer open mode. This pathway is the major contributor to the generation of mIcat, but is inactive when either the M2 or M3 receptor is absent, or when either Go, Gq/11 or PLC is inactivated. In other words, the activity of this pathway is conditional, occurring only when both M2/Go and M3/Gq/11 signalling pathways are activated. Studies of mAChR-KO mice [23,44] and TRPC-mutant mice [42] indicate that these 70-pS and 120-pS cationic channel activities are mediated by TRPC4 and TRPC6, respectively. The M2/M3 pathway, but not the M2 or M3 pathway, involves a signalling step in which Ca2+ has a potentiating effect on TRPC channel activation, suggesting that the M3 pathway may facilitate M2/M3 pathway function through InsP3-induced Ca2+ release. Whether the M2/M3 pathway has a significant role in stimulating InsP3/DAG formation or inhibiting cAMP accumulation is currently unclear. One study suggested that Go protein is not involved in adenylyl cyclase inhibition by M2 receptors of intestinal smooth muscle [24]. These three pathways may also converge on voltage-dependent Ca2+ channels (VDCCs) to suppress Ca2+ influx via the same G-protein pathways mediating cationic channel activation (see Figure 10B in Tanahashi et al., 2009 [49]).