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The Journal of Neuroscience, December 15, 2002, 22(24):10627-10632

Mice Lacking M₂ and M₃ Muscarinic Acetylcholine Receptors Are Devoid of Cholinergic Smooth Muscle Contractions But Still Viable

Minoru Matsui^{1, 2}, Daisuke Motomura², Toru Fujikawa³, Jian Jiang³, Shin-ichi Takahashi², Toshiya Manabe¹, and Makoto M. Taketo^{2, 4}

¹ Division of Neuronal Network, Department of Basic Medical Sciences, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan, ² Laboratory of Biomedical Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan, and ³ Banyu Tsukuba Research Institute (Merck), Ibaraki 300-2611, Japan, and ⁴ Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan

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 vitro was ~5 and 95% for the detrusor muscle contraction and ~25 and 75% for the ileal longitudinal muscle contraction, respectively. Thus, M₁, M₄, or M₅ receptors 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.

Key words: acetylcholine; muscarinic receptors; smooth muscle contraction; gene targeting; intestinal motility; ocular pupils

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Copyright © 2002 Society for Neuroscience  0270-6474/02/222410627-06$05.00/0

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