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Originally published In Press as doi:10.1074/jbc.M011233200 on February 14, 2001

J. Biol. Chem., Vol. 276, Issue 19, 15801-15809, May 11, 2001
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The G Protein beta  Subunit Is a Determinant in the Coupling of Gs to the beta 1-Adrenergic and A2a Adenosine Receptors*

William E. McIntireDagger , Gavin MacCleery, and James C. Garrison

From the Department of Pharmacology, University of Virginia Health System, Charlottesville, Virginia 22908

The signaling specificity of five purified G protein beta gamma dimers, beta 1gamma 2, beta 2gamma 2, beta 3gamma 2, beta 4gamma 2, and beta 5gamma 2, was explored by reconstituting them with Gs alpha  and receptors or effectors in the adenylyl cyclase cascade. The ability of the five beta gamma dimers to support receptor-alpha -beta gamma interactions was examined using membranes expressing the beta 1-adrenergic or A2a adenosine receptors. These receptors discriminated among the defined heterotrimers based solely on the beta  isoform. The beta 4gamma 2 dimer demonstrated the highest coupling efficiency to either receptor. The beta 5gamma 2 dimer coupled poorly to each receptor, with EC50 values 40-200-fold higher than those observed with beta 4gamma 2. Strikingly, whereas the EC50 of the beta 1gamma 2 dimer at the beta 1-adrenergic receptor was similar to beta 4gamma 2, its EC50 was 20-fold higher at the A2a adenosine receptor. Inhibition of adenylyl cyclase type I (AC1) and stimulation of type II (AC2) by the beta gamma dimers were measured. beta gamma dimers containing Gbeta 1-4 were able to stimulate AC2 similarly, and beta 5gamma 2 was much less potent. beta 1gamma 2, beta 2gamma 2, and beta 4gamma 2 inhibited AC1 equally; beta 3gamma 2 was 10-fold less effective, and beta 5gamma 2 had no effect. These data argue that the beta  isoform in the beta gamma dimer can determine the specificity of signaling at both receptors and effectors.

* This work was supported in part by National Institutes of Health Grant RO1-DK-19952.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.

Dagger Supported by a National Institutes of Health fellowship in Diabetes and Hormone Action. To whom correspondence should be addressed: Dept. of Pharmacology, University of Virginia Health System, P. O. Box 800735, 1300 Jefferson Park Ave., Charlottesville, VA 22908. Tel.: 804-924-9976; Fax: 804-924-5207; E-mail: wem2p@virginia.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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