Pharmacological Analysis of the Contractile Role of M 2 and M 3 Muscarinic Receptors in Smooth Muscle

Abstract

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 Ca 2+ . 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.