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Volume 272, Number 34, Issue of August 22, 1997 pp. 21317-21324
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Differential Coupling of Muscarinic m₂ and m₃ Receptors to Adenylyl Cyclases V/VI in Smooth Muscle
CONCURRENT m₂-MEDIATED INHIBITION VIA G_i3 AND m₃-MEDIATED STIMULATION VIA G_q

(Received for publication, February 27, 1997, and in revised form, June 18, 1997)

From the Departments of Physiology and Medicine, Medical College of Virginia, Richmond, Virginia 23298-0711

Muscarinic m₂ and m₄ receptors couple preferentially to inhibition of adenylyl cyclase, whereas m₁, m₃, and m₅ receptors couple preferentially to activation of phospholipase C- and in some cells to stimulation of cAMP. Smooth muscle cells were shown to express adenylyl cyclases types V and/or VI. Acetylcholine (ACh) stimulated the binding of [³⁵S]GTPS·G complexes in smooth muscle membranes to G_q/11 and G_i3 antibody. Binding to G_q/11 antibody was inhibited by the m₃ receptor antagonist, 4-DAMP, and binding to G_i3 antibody was inhibited by the m₂ receptor antagonist, N,N-bis[6[[(2-methoxyphenyl)methyl]amino]hexyl]-1,8-octanediamine tetrahydrochloride (methoctramine). The decrease in basal cAMP (35 ± 5%) induced by ACh in dispersed muscle cells was accentuated by 4-DAMP or G antibody (55 ± 8 to 63 ± 6%). In contrast, methoctramine, pertussis toxin (PTx), or G_i3 antibody converted the decrease in cAMP to increase above basal level (+28 ± 5 to +32 ± 6%); the increase in cAMP was abolished by 4-DAMP or G antibody. In muscle cells where only m₃ receptors were preserved by selective receptor protection, ACh caused only an increase in cAMP that was abolished by 4-DAMP. Conversely, in muscle cells where only m₂ receptors were preserved, ACh caused an accentuated decrease in cAMP that was abolished by methoctramine or PTx. In conclusion, m₂ receptors in smooth muscle couple to inhibition of adenylyl cyclases V/VI via G_i3, and m₃ receptors couple to activation of the enzymes via G_q/11.

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