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 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.
Ehlert
Frederick J
FJ
Department of Pharmacology, College of Medicine, University of California, Irvine, Irvine, California 92697-4625, USA. fjehlert@uci.edu
D000818:Animals; D006801:Humans; D009119:Muscle Contraction / Q000502:physiology* / Q000528:radiation effects; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D043585:Receptor, Muscarinic M2 / Q000819:agonists / Q000187:drug effects / Q000502:physiology*; D043587:Receptor, Muscarinic M3 / Q000819:agonists / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D009125:Muscle Relaxants, Central; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3