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Vol. 295, Issue 3, 879-888, December 2000

Pharmacological and Molecular Characterization of Muscarinic Receptor Subtypes in Human Esophageal Smooth Muscle1

Harold G. Preiksaitis2 , Pawel S. Krysiak , Tom Chrones, Vaishnav Rajgopal and Lisanne G. Laurier

Departments of Medicine (H.G.P., L.G.L.) and Physiology (H.G.P., P.S.K.), The University of Western Ontario, London, Ontario, Canada; and The Lawson Research Institute, St. Joseph's Health Centre of London, Department of Medicine, London, Ontario, Canada (H.G.P., P.S.K., T.C., V.R., L.G.L.)

Esophageal peristalsis is dependent on activation of muscarinic receptors, but little is known about the roles of specific receptor subtypes in the human esophagus. We examined muscarinic receptor expression and function in human esophageal smooth muscle obtained from patients undergoing resection for cancer. [3H]Quinuclidinyl benzylate (QNB)-specific binding was similar in longitudinal muscle (Bmax = 106 ± 22 fmol/mg of protein, Kd = 68 ± 9 pM) and circular muscle (Bmax = 81 ± 16 fmol/mg of protein, Kd = 79 ± 15 pM). Subtype-selective antagonists inhibited [3H]QNB similarly in muscle from both layers. Further analysis of antagonist inhibition of [3H]QNB binding showed a major site (60-70%) with antagonist affinity profile consistent with the M2 subtype and a second site that could not be classified. Reverse transcription-polymerase chain reaction and immunoblotting demonstrated the presence of all five known muscarinic receptor subtypes, and immunocytochemistry on acutely isolated smooth muscle cells confirmed the expression of each subtype on the muscle cells. Subtype-selective antagonists had similar inhibitory effects on carbachol-evoked contractions in longitudinal muscle and circular muscle strips with pA2 values of 9.5 ± 0.1 and 9.6 ± 0.2 for 4-diphenylacetoxy-N-methylpiperidine methiodide, 7.1 ± 0.1 and 7.0 ± 0.2 for pirenzepine, and 6.2 ± 0.2 and 6.4 ± 0.2 for methoctramine, respectively. We conclude that human esophageal smooth muscle expresses muscarinic receptor subtypes M1 through M5. The antagonist sensitivity profile for muscle contraction is consistent with activation of the M3 subtype.

1 This work was supported by the Medical Research Council of Canada.

2 H.G.P. is a recipient of an Ontario Ministry of Health Career Scientist Award.

0022-3565/00/2953-0879$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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