PT - JOURNAL ARTICLE AU - Michael T. Griffin AU - Minoru Matsui AU - Darakhshanda Shehnaz AU - Khurram Z. Ansari AU - Makoto M. Taketo AU - Toshiya Manabe AU - Frederick J. Ehlert TI - Muscarinic Agonist-Mediated Heterologous Desensitization in Isolated Ileum Requires Activation of Both Muscarinic M<sub>2</sub> and M<sub>3</sub> Receptors AID - 10.1124/jpet.103.055327 DP - 2004 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 339--349 VI - 308 IP - 1 4099 - http://jpet.aspetjournals.org/content/308/1/339.short 4100 - http://jpet.aspetjournals.org/content/308/1/339.full SO - J Pharmacol Exp Ther2004 Jan 01; 308 AB - 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 F2α (PGF2α) 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 PGF2α 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. The American Society for Pharmacology and Experimental Therapeutics