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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

The Use of Occupation Isoboles for Analysis of a Response Mediated by Two Receptors: M₂ and M₃ Muscarinic Receptor Subtype-Induced Mouse Stomach Contractions

Departments of Urology (A.S.B., M.R.R.) and Pharmacology (R.J.T., M.R.R.), Temple University School of Medicine, Philadelphia, Pennsylvania

Smooth muscle contains multiple muscarinic receptor subtypes, including M₂ and M₃. M₂ receptors outnumber M₃ receptors. Based on the potency of subtype selective anticholinergics, contraction is mediated by the M₃ subtype. However, results from knockout (KO) mice show that the M₂ receptor mediates approximately 45% of the contractile response produced by the M₃ receptor. The traditional theory of one receptor mediating a response does not allow assessment of interactions between receptors when more than one receptor participates in a response. Our study was performed using a novel analysis method based on dual receptor occupancy to determine how M₂ and M₃ receptor subtypes interact to mediate contraction in mouse stomach. Cumulative carbachol concentration contractile responses were determined for wild-type, M₂-KO, and M₃-KO stomach body smooth muscle. Using affinity constants for carbachol at M₂ and M₃ cholinergic receptors, the concentration values were converted to fractional receptor occupation. The resulting occupation-effect relations showed maximum effects for the M₂ and M₃ subtypes, respectively. These occupation-effect relations allow determination of the additive (expected) isobole based on this dual occupancy, thereby providing a curve (mathematically derived) for comparison against the experimentally derived value in wild type. The actual values determined experimentally in the wild type were not statistically significantly different from that predicted by the isobole. This confirms that the interaction between these mutually occupied receptors is additive. The new method of analysis also expands the traditional Schild theory that was based on a single receptor type to which the agonist and antagonist bind.

Address correspondence to: Dr. Michael R. Ruggieri, Sr., Temple University School of Medicine, 715 OMS, 3400 North Broad Street, Philadelphia, PA 19140. E-mail: rugg{at}temple.edu

This article has been cited by other articles:

				A. S. Braverman, L. S. Miller, A. K. Vegesna, M. I. Tiwana, R. J. Tallarida, and M. R. Ruggieri Sr. Quantitation of the Contractile Response Mediated by Two Receptors: M2 and M3 Muscarinic Receptor-Mediated Contractions of Human Gastroesophageal Smooth Muscle J. Pharmacol. Exp. Ther., April 1, 2009; 329(1): 218 - 224. [Abstract] [Full Text] [PDF]