9.A.14.3.2
The muscarinic acetylcholine G-protein-coupled receptor (Jo et al., 2010). Endothelial-dependent muscarinic receptor signaling acts largely through TRPV4 sparklet-mediated stimulation of IK (1.A.1.16.2) and SK (1.A.1.16.1) channels to promote vasodilation. There are five muscarinic receptor subtypes (M1R to M5R), which, despite sharing a high degree of sequence identity in the transmembrane region, couple to different heterotrimeric G proteins to transmit signals. M1R, M3R, and M5R couple to the G_{q/ 11} family, whereas M2R and M4R couple to the G_{i/ o} family. Maeda et al. 2019 presented and compared the cryo-electron microscopy structures of M1R in complex with G₁₁ and M2R in complex with G_oA. The M1R-G₁₁ complex exhibits distinct features, including an extended transmembrane helix 5 and carboxyl-terminal receptor tail that interacts with the G protein. Detailed analysis provides a framework for understanding the molecular determinants of G-protein coupling selectivity (Maeda et al. 2019). The affinity of the seven-transmembrane muscarinic acetylcholine receptors for their agonists is modulated by membrane depolarization. Possibly this characteristic. Experiments measuring acetylcholine binding to muscarinic receptors in brain synaptoneurosomes suggest that gating of the voltage-dependent sodium channel (VDSC) acts as the voltage sensor, generating activation of Go-proteins in response to membrane depolarization, and this modulates the affinity of muscarinic receptors for their cholinergic agonists (Cohen-Armon 2023).