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CELLULAR AND MOLECULAR

The M₂ Muscarinic Receptor Mediates Contraction through Indirect Mechanisms in Mouse Urinary Bladder

Department of Pharmacology, College of Medicine, University of California, Irvine, Irvine, California (F.J.E., D.M.A., T.H.V.); Department of Physical Sciences, Chapman University, Orange, California (M.T.G.); Department of Pharmacology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan (M.M.T.); Division of Neuronal Network, Department of Basic Medical Sciences, the Institute of Medical Science, the University of Tokyo, Minato-ku, Tokyo, Japan (T.M.); and Laboratory of Biomedical Genetics, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Bunkyo-ku, Tokyo, Japan (M.M.)

We investigated the contractile role of M₂ muscarinic receptors in mouse urinary bladder. When measured in the absence of other agents, contractions elicited to the muscarinic agonist oxotremorine-M exhibited properties consistent with that expected for an M₃ response in urinary bladder from wild-type and M₂ knockout (KO) mice. Evidence for a minor M₂ receptor-mediated contraction was revealed by a comparison of responses in M₃ knockout and M₂/M₃ double knockout mice. Treatment of wild-type and M₂ knockout urinary bladder with N-2-chloroethyl-4-piperidinyl diphenylacetate (4-DAMP mustard) caused a large inhibition of the muscarinic contractile response. The residual contractions were much smaller in M₂ knockout bladder compared with wild type, suggesting that M₂ receptors rescue the muscarinic contractile response in wild-type bladder following inactivation of M₃ receptors with 4-DAMP mustard. When measured in the presence of prostaglandin F₂ and isoproterenol or forskolin, oxotremorine-M mediated a potent contractile response in urinary bladder from M₃ KO mice. This response exhibited an M₂ profile in competitive antagonism studies and was completely absent in M₂/M₃ KO mice. Following 4-DAMP mustard treatment, oxotremorine-M elicited a contractile response in wild-type urinary bladder in the presence of KCl and isoproterenol or forskolin, and this response was diminished in M₂ KO mice. Our results show that the M₂ receptor mediates contractions indirectly in the urinary bladder by enhancing M₃ receptor-mediated contractions and inhibiting relaxation. We also show that it is difficult to detect M₂ receptor function in competitive antagonism studies under conditions where a simultaneous activation of M₂ and M₃ receptors occurs.

Address correspondence to: Dr. Frederick J. Ehlert, Department of Pharmacology, University of California Irvine, Irvine, CA 92697-4625. E-mail: fjehlert{at}uci.edu

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