Ehlert_2012_Handb.Exp.Pharmacol_208_343

Muscarinic agonists and antagonists are used to treat a handful of gastrointestinal (GI) conditions associated with impaired salivary secretion or altered motility of GI smooth muscle. With regard to exocrine secretion, the major muscarinic receptor expressed in salivary, gastric, and pancreatic glands is the M(3) with a small contribution of the M(1) receptor. In GI smooth muscle, the major muscarinic receptors expressed are the M(2) and M(3) with the M(2) outnumbering the M(3) by a ratio of at least four to one. The antagonism of both smooth muscle contraction and exocrine secretion is usually consistent with an M(3) receptor mechanism despite the major presence of the M(2) receptor in smooth muscle. These results are consistent with the conditional role of the M(2) receptor in smooth muscle. That is, the contractile role of the M(2) receptor depends on that of the M(3) so that antagonism of the M(3) receptor eliminates the response of the M(2). The physiological roles of muscarinic receptors in the GI tract are consistent with their known signaling mechanisms. Some so-called tissue-selective M(3) antagonists may owe their selectivity to a highly potent interaction with a nonmuscarinic receptor target.