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Originally published In Press as doi:10.1074/jbc.M203640200 on June 13, 2002

J. Biol. Chem., Vol. 277, Issue 34, 31257-31262, August 23, 2002
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Age Increases Cardiac Galpha i2 Expression, Resulting in Enhanced Coupling to G Protein-coupled Receptors*

Jason D. KiltsDagger , Toshimasa AkazawaDagger , Mark D. RichardsonDagger §, and Madan M. KwatraDagger §||

From the Departments of Dagger  Anesthesiology and  Pharmacology and Cancer Biology and the § Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, North Carolina 27710

Cardiac G protein-coupled receptors that function through stimulatory G protein Galpha s, such as beta 1- and beta 2-adrenergic receptors (beta 1ARs and beta 2ARs), play a key role in cardiac contractility. Recent data indicate that several Galpha s-coupled receptors in heart also activate Galpha i, including beta 2ARs (but not beta 1ARs). Coupling of cardiac beta 2ARs to Galpha i inhibits adenylyl cyclase and opposes beta 1AR-mediated apoptosis. Dual coupling of beta 2AR to both Galpha s and Galpha i is likely to alter beta 2AR function in disease, such as congestive heart failure in which Galpha i levels are increased. Indeed, heart failure is characterized by reduced responsiveness of beta ARs. Cardiac beta AR-responsiveness is also decreased with aging. However, whether age increases cardiac Galpha i has been controversial, with some studies reporting an increase and others reporting no change. The present study examines Galpha i in left ventricular membranes from young and old Fisher 344 rats by employing a comprehensive battery of biochemical assays. Immunoblotting reveals significant increases with age in left ventricular Galpha i2, but no changes in Galpha i3, Galpha o, Galpha s, Gbeta 1, or Gbeta 2. Aging also increases ADP-ribosylation of pertussis toxin-sensitive G proteins. Consistent with these results, basal as well as receptor-mediated incorporation of photoaffinity label [32P]azidoanilido-GTP indicates higher amounts of Galpha i2 in older left ventricular membranes. Moreover, both basal and receptor-mediated adenylyl cyclase activities are lower in left ventricular membranes from older rats, and disabling of Galpha i with pertussis toxin increases both basal and receptor-stimulated adenylyl cyclase activity. Finally, age produces small but significant increases in muscarinic potency for the inhibition of both beta 1AR- and beta 2AR-stimulated adenylyl cyclase activity. The present study establishes that Galpha i2 increases with age and provides data indicating that this increase dampens adenylyl cyclase activity.

* This study was supported in part by National Institutes of Health Grants AG15817 (to M. M. K.) and 5 T32 AG00024 (to M. D. R.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

|| To whom correspondence should be addressed: Dept. of Anesthesiology, 146 Sands Bldg., Box 3094, Duke University Medical Center, Durham, NC 27710. Tel.: 919-681-4775; Fax: 919-681-8089; E-mail: kwatr001@mc.duke.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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