Mice Lacking M2and M3Muscarinic Acetylcholine Receptors Are Devoid of Cholinergic Smooth Muscle Contractions But Still Viable

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Abstract
Cholinergic agents elicit prominent smooth muscle contractions via stimulation of muscarinic receptors that comprise five distinct subtypes (M1–M5). Although such contractions are important for autonomic organs, the role of each subtype has not been characterized precisely because of the poor selectivity of the currently available muscarinic ligands. Here, we generated a mutant mouse line (M2−/−M3−/− mice) lacking M2 and M3 receptors that are implicated in such cholinergic contractions. The relative contributions of M2 and M3 receptors in vitrowas ∼5 and 95% for the detrusor muscle contraction and ∼25 and 75% for the ileal longitudinal muscle contraction, respectively. Thus, M1, M4, or M5receptors do not seem to play a role in such contractions. Despite the complete lack of cholinergic contractions in vitro, M2−/−M3−/− mice were viable, fertile, and free of apparent intestinal complications. The urinary bladder was distended only in males, which excludes a major contribution by cholinergic mechanisms to the urination in females. Thus, cholinergic mechanisms are dispensable in gastrointestinal motility and female urination. After 10 Hz electrical field stimulation, noncholinergic inputs were found to be increased in the ileum of M2−/−M3−/− females, which may account for the lack of apparent functional deficits. Interestingly, the M2−/−M3−/− mice had smaller ocular pupils than M3-deficient mice. The results suggest a novel role of M2 in the pupillary dilation, contrary to the well known cholinergic constriction. These results collectively suggest that an additional mechanism operates in the control of pupillary constriction–dilatation.