mAChR3

The M3 muscarinic acetylcholine receptor (M3-mAChR) is a G protein-coupled receptor that regulates diverse physiological processes, including smooth muscle contraction, glandular secretion, and cardiac function^[1][2][3]. Mechanistically, M3-mAChR activation primarily signals through Gq proteins, inducing phospholipase C-β (PLC-β) activation, inositol trisphosphate (InsP₃) generation, and intracellular Ca²⁺ release^[4][5]. In airway smooth muscle cells, biased ligands such as PD 102807 mediate AMPK-dependent inhibition of mTORC1, attenuating TGF-β-induced hypercontractile phenotypes, whereas balanced agonists induce calcium-dependent AMPK signaling^[2]. In cardiomyocytes, M3-mAChR stimulation delays cardiac aging by suppressing caspase-1/IL-1β signaling and modulating the miR-29b/BACE1 axis, reducing fibrosis and cell proliferation^[6][7]. M3-mAChR is also implicated in tumorigenesis, facilitating epithelial-mesenchymal transition, perineural invasion, and angiogenesis via AKT and nitric oxide synthase pathways^[8][9]. Compared with other muscarinic receptor isoforms, M3 exhibits unique coupling to multiple G protein families and distinctive regulatory motifs, such as NPxxY, which govern receptor signaling and multiprotein complex formation^[1][10]. Functionally, selective agonists like choline and pilocarpine and inhibitors such as 4-DAMP allow experimental modulation of M3-mAChR activity, supporting disease modeling and therapeutic investigations in cardiovascular, respiratory, and oncological contexts^{[6][9][7][11]}. Moreover, M3-mAChR forms microdomains with InsP₃ receptors, creating localized Ca²⁺ signaling junctions critical for wave initiation in smooth muscle cells^[5]. These properties distinguish M3-mAChR from other isoforms and facilitate its utility in mechanistic and pharmacological research.