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(Circulation Research. 2000;87:705.)
© 2000 American Heart Association, Inc.

Molecular Medicine

ß₂-Adrenergic and Several Other G Protein–Coupled Receptors in Human Atrial Membranes Activate Both G_s and G_i

Presented in part at the 1998 Annual Meeting of the American Society of Anesthesiologists, Orlando, Fla, October 17–21, 1998.

Jason D. Kilts, Mark A. Gerhardt, Mark D. Richardson, Gautam Sreeram, G. Burkhard Mackensen, Hilary P. Grocott, William D. White, R. Duane Davis, Mark F. Newman, Joseph G. Reves, Debra A. Schwinn, Madan M. Kwatra

From the Departments of Anesthesiology (J.D.K., M.D.R., G.S., G.B.M., H.P.G., W.D.W., M.F.N., J.G.R., D.A.S., M.M.K.), Pharmacology and Cancer Biology (D.A.S., M.M.K.), and Surgery (R.D.D., D.A.S.), Duke University Medical Center, Durham, NC; and Department of Anesthesiology (M.A.G.), Ohio State University, Columbus, Ohio.

Correspondence to Madan M. Kwatra, PhD, Department of Anesthesiology, 146 Sands Bldg, Box 3094, Duke University Medical Center, Durham, NC 27710. E-mail kwatr001{at}mc.duke.edu

Abstract—Cardiac G protein–coupled receptors that couple to G_s and stimulate cAMP formation (eg, ß-adrenergic, histamine, serotonin, and glucagon receptors) play a key role in cardiac inotropy. Recent studies in rodent cardiac myocytes and transfected cells have revealed that one of these receptors, the ß₂-adrenergic receptor (AR), also couples to the inhibitory G protein G_i (activation of which inhibits cAMP formation). If ß₂ARs could be shown to couple to G_i in the human heart, it would have important ramifications, because levels of G_i increase with age and in failing human heart. Therefore, we investigated whether ß₂ARs in the human heart activate G_i. By photoaffinity labeling human atrial membranes with [³²P]azidoanilido-GTP, followed by immunoprecipitation with antibodies specific for G_i, we found that G_i is activated by stimulation of ß₂ARs but not of ß₁ARs. In addition, we found that other G_s-coupled receptors also couple to G_i, including histamine, serotonin, and glucagon. When coupling of these receptors to G_i is disrupted by pertussis toxin, their ability to stimulate adenylyl cyclase is enhanced. These data provide the first evidence that ß₂AR and many other G_s-coupled receptors in human atrium also couple to G_i and that abolishing the coupling of these receptors to G_i increases the receptor-mediated adenylyl cyclase activity.

Key Words: human atrial G_s and G_i • ß₂-adrenergic receptor • cardiac G_s–coupled receptors

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