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CELLULAR AND MOLECULAR

Differential Coupling of Muscarinic M₁, M₂, and M₃ Receptors to Phosphoinositide Hydrolysis in Urinary Bladder and Longitudinal Muscle of the Ileum of the Mouse

Department of Pharmacology, College of Medicine, University of California, Irvine, California (J.A.T., F.J.E.); and Division of Neuronal Network, Department of Basic Medical Sciences, the Institute of Medical Science, the University of Tokyo, Minato-ku, Tokyo, Japan (M.M.)

We investigated the coupling of muscarinic receptor (M) subtypes to phosphoinositide hydrolysis in ileum and urinary bladder using muscarinic receptor knockout mice. In urinary bladder from wild-type mice, the muscarinic agonist oxotremorine-M, elicited a robust phosphoinositide response characterized by an EC₅₀ value of 0.22 µM and a maximal response (E_max) of 32.8% conversion of [³H]inositol-labeled phosphoinositides into [³H]inositol phosphates. A similar response was observed in urinary bladder from M₂ knockout mice, whereas no measurable response was observed in urinary bladder from M₃ and M₂/M₃ knockout mice. In ilea from wild-type and M₂ knockout mice, substantial phosphoinositide responses to oxotremorine-M were measured, characterized by EC₅₀ values of 0.37 and 0.52 µM and E_max values of 35.8 and 34.7%, respectively. Oxotremorine-M also elicited phosphoinositide hydrolysis in ilea from M₃ and M₂/M₃ knockout mice, although these responses were less sensitive (EC₅₀ values of 1.6 and 1.4 µM; E_max values of 31.2 and 20.8%, respectively). The response in ileum from the M₂/M₃ knockout was significantly smaller than that from the M₃ knockout. The muscarinic phosphoinositide response in ilea from M₂/M₃ knockout mice originated in the smooth muscle and exhibited a profile for competitive antagonism consistent with an M₁ mechanism. These data suggest a major role for the M₃ receptor in eliciting phosphoinositide hydrolysis in the ileum and urinary bladder and minor roles for the M₁ and M₂ in ileum.

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

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