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J. Biol. Chem., Vol. 281, Issue 38, 28222-28231, September 22, 2006

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R7BP Augments the Function of RGS7·G5 Complexes by a Plasma Membrane-targeting Mechanism^*

Ryan M. Drenan¹, Craig A. Doupnik, Muralidharan Jayaraman, Abigail L. Buchwalter, Kevin M. Kaltenbronn, James E. Huettner, Maurine E. Linder, and Kendall J. Blumer²

From the Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110 and the Department of Physiology and Biophysics, University of South Florida College of Medicine, Tampa, Florida 33612

The RGS7 (R7) family of G protein regulators, G5, and R7BP form heterotrimeric complexes that potently regulate the kinetics of G protein-coupled receptor signaling. Reversible palmitoylation of R7BP regulates plasma membrane/nuclear shuttling of R7·G5·R7BP heterotrimers. Here we have investigated mechanisms whereby R7BP controls the function of the R7 family. We show that unpalmitoylated R7BP undergoes nuclear/cytoplasmic shuttling and that a C-terminal polybasic motif proximal to the palmitoylation acceptor sites of R7BP mediates nuclear localization, palmitoylation, and plasma membrane targeting. These results suggest a novel mechanism whereby palmitoyltransferases and nuclear import receptors both utilize the C-terminal domain of R7BP to determine the trafficking fate of R7·G5·R7BP heterotrimers. Analogous mechanisms may regulate other signaling proteins whose distribution between the plasma membrane and nucleus is controlled by palmitoylation. Lastly, we show that cytoplasmic RGS7·G5·R7BP heterotrimers and RGS7·G5 heterodimers are equivalently inefficient regulators of G protein-coupled receptor signaling relative to plasma membrane-bound heterotrimers bearing palmitoylated R7BP. Therefore, R7BP augments the function of the complex by a palmitoylation-regulated plasma membrane-targeting mechanism.

Received for publication, May 9, 2006 , and in revised form, July 20, 2006.

^* This work was supported by National Institutes of Health Grants NS30888 (to J. E. H.), GM51466 (to M. E. L.), and GM44592 and HL075632 (to K. J. B.) and funds from the American Heart Association, Florida and Puerto Rico Affiliate (to C. A. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by American Heart Association Predoctoral Fellowship 04153107Z.

² To whom correspondence should be addressed: Dept. of Cell Biology and Physiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-1668; Fax: 314-362-7463; E-mail: kblumer{at}cellbiology.wustl.edu.

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