Figure 2.

Overview of post-receptor acetylcholine (ACh) signaling. Odd-numbered muscarinic receptors (M_odd: M₁R, M₃R, and M₅R) are coupled to G_q/11 signaling, which effects cellular change via phospholipid metabolism and increasing intracellular calcium concentrations, while even-numbered muscarinic receptors (M_even: M₂R and M₄R) are coupled to G_i/o, which inhibits the formation of cAMP by membrane-bound adenylyl cyclase (AC). As a result of M_even signaling, protein kinase C (PKC) is activated, which further activates mitogen-activated protein kinases (MAPK), such as p38 mitogen-activated protein kinase (MAPK) and extracellular signal-related kinase-1/2 (ERK1/2), to alter gene expression. ACh-bound M_odd also transactivates epidermal growth factor receptors (EGFR) via activation of matrix metalloproteinases (MMP), offering another mechanism whereby ERK1/2 can be activated. M_even activation is not known to directly transactivate EGFR, and instead leads to the inhibition of the activation of EGFR by protein kinase A (PKA). Nicotinic signaling is diverse and subtype-dependent. α7nAChR activates AC, leading to upregulation of cAMP production and PKA activation, both directly and through interplay with β-adrenergic receptors (β-AR). Muscarinic and nicotinic cholinergic receptors can also recruit β-arrestins, which mediate receptor internalization. Created with BioRender.com.