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CELLULAR AND MOLECULAR

Muscarinic Agonist-Mediated Heterologous Desensitization in Isolated Ileum Requires Activation of Both Muscarinic M₂ and M₃ Receptors

Department of Physical Sciences, Chapman University, Orange, California (M.T.G.); Laboratory of Biomedical Genetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan (M.M., M.M.T.); Department of Pharmacology, College of Medicine, University of California, Irvine, Irvine, California (D.S., K.Z.A., F.J.E.); and Division of Neural Network, Department of Basic Medical Sciences, University of Tokyo, Tokyo, Japan (T.M.)

We investigated the subtypes of the muscarinic receptor mediating short-term heterologous desensitization in the isolated ileum. Treatment of the ileum from C57BL/6 mice with acetylcholine (30 µM) for 20 min caused a subsequent decrease in contractile sensitivity to both prostaglandin F₂ (PGF₂) and the muscarinic agonist, oxotremorine-M. This subsensitivity was characterized by 7- and 3-fold increases in the EC₅₀ values of the agonists, respectively, with no significant effect on the maximal response. The subsensitivity to PGF₂ was prevented in both M₂ and M₃ muscarinic receptor knockout mice. Similarly, the subsensitivity to oxotremorine-M was prevented in M₂ knockout mice. Acetylcholine-mediated desensitization of histamine-induced contractions in the guinea pig ileum was inhibited by both M₂- and M₃-selective muscarinic antagonists with high potency, although careful analysis of the data suggested behavior more consistent with an M₂ antagonistic profile. Modeling studies showed that the competitive antagonism of response contingent upon activation of two receptor subtypes should exhibit a pharmacological profile similar to that of the least sensitive signaling pathway. Our results demonstrate that muscarinic agonist-mediated short-term heterologous desensitization of intestinal smooth muscle is contingent upon activation of both M₂ and M₃ muscarinic receptors and that activation of either receptor by itself is insufficient to cause desensitization.

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

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