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

• Published in: Life sciences (1973) Vol. 74; no. 2-3; pp. 355 - 366
• Main Author: Ehlert, Frederick J
• Format: Journal Article
• Language: English
• Published: Netherlands 05.12.2003
• Subjects: Animals; Binding, Competitive - drug effects; Cyclic AMP - metabolism; Digestive System Physiological Phenomena; Humans; Muscarinic Antagonists - pharmacology; Muscle Contraction - drug effects; Muscle Contraction - physiology; Muscle Relaxation - drug effects; Muscle, Smooth - drug effects; Muscle, Smooth - metabolism; Muscle, Smooth - physiology; Receptor, Muscarinic M2 - drug effects; Receptor, Muscarinic M2 - physiology; Receptor, Muscarinic M3 - drug effects; Receptor, Muscarinic M3 - physiology; Respiratory Physiological Phenomena; Urinary Bladder - physiology
• ISSN: 0024-3205
• DOI: 10.1016/j.lfs.2003.09.023

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, Ca(2+) mobilization and a direct contractile response. In contrast, M(2) receptors interact with G(i) and G(o) to inhibit adenylyl cyclase and Ca(2+)-activated K(+) channels and to potentiate a Ca(2+)-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 Ca(2+) 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 M(2) and M(3) receptors.