Contractile role of M2 and M3 muscarinic receptors in gastrointestinal, airway and urinary bladder smooth muscle

Both M-2 and M-3 muscarinic receptors are expressed in smooth muscle and influence contraction through distinct signaling pathways. M-3 receptors interact with G(q) to trigger phosphoinositide hydrolysis, Ca2+ mobilization and a direct contractile response. In contrast, M-2 receptors interact with G(i) and G(o) to inhibit adenylyl cyclase and Ca2+-activated K+ channels and to potentiate a Ca2+ -dependent, nonselective cation conductance. Ultimately, these mechanisms lead to the prediction that the influence of the M-2 receptor on contraction should be conditional upon mobilization of Ca2+ by another receptor such as the M-3. Mathematical modeling studies of these mechanisms show that the competitive antagonism of a muscarinic response mediated through activation of both M-2 and M-3 receptors should resemble the profile of the directly acting receptor (i.e., the M-3) and not that of the conditionally acting receptor (i.e., the M-2). Using a combination of pharmacological and genetic approaches, we have identified two mechanisms for the M-2 receptor in contraction: 1) a high potency inhibition of the relaxation elicited by agents that increase cytosolic cAMP and 2) a low potency potentiation of contractions elicited by the M-3 receptor. The latter mechanism may be involved in muscarinic agonist-mediated heterologous desensitization of smooth muscle, which requires activation of both M2 and M3 receptors. (C) 2003 Elsevier Inc. All rights reserved.