Pharmacological analysis of the contractile role of M2 and M3 muscarinic receptors in smooth muscle

Muscarinic receptors expressed on smooth muscle cells are primarily of the M-2 and M-3 subtypes. The M-3 subtype triggers contraction through an interaction with G(q) proteins to stimulate phosphoinositide hydrolysis and mobilize Ca2+. In contrast, activation of M-2 receptors modulates contraction by preventing relaxation or by potentiating M-3 receptor-mediated contractions, which enhances heterologous desensitization. These effects can be explained by the coupling of M-2 receptors to G(i) proteins that mediate an inhibition of adenylyl cyclase and calcium-activated potassium channels. The pharmacological antagonism of a response mediated through an interaction between M-2 and M-3 receptors has been shown to resemble the profile of the directly acting receptor (M-3), primarily, and not that of the conditional receptor (M-2). Evidence for a contractile role of the M-2 receptor has been obtained by inactivating its signaling pathway with pertussis toxin or by measuring contractile effects of muscarinic agonists after M-3 receptors have been covalently inactivated. Under these conditions, M-2 receptors have been shown to mediate an inhibition of the relaxant effects of agents, like isoproterenol, on the contractile effects of nonmuscarinic spasmogens. Muscarinic M-2 and M-3 receptor knockout mice are useful tools for exploring interactions between these receptors in smooth muscle.