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J. Biol. Chem., Vol. 282, Issue 18, 13703-13715, May 4, 2007

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Dopamine Receptor-interacting Protein 78 Acts as a Molecular Chaperone for G Subunits before Assembly with G^*

Denis J. Dupré¹, Mélanie Robitaille, Maxime Richer, Nathalie Éthier, Aida M. Mamarbachi^¶, and Terence E. Hébert²

From the Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, H3G 1Y6, Canada, Département de Biochimie, Université de Montréal, Montréal, Québec, H3C 3J7, Canada, and the ^¶Institut de Cardiologie de Montréal, Québec, H1T 1C8, Canada

Heterotrimeric G proteins play a central role in intracellular communication mediated by extracellular signals, and both G and G subunits regulate effectors downstream of activated receptors. The particular constituents of the G protein heterotrimer affect both specificity and efficiency of signal transduction. However, little is known about mechanistic aspects of G protein assembly in the cell that would certainly contribute to formation of heterotrimers of specific composition. It was recently shown that phosducin-like protein (PhLP) modulated both G expression and subsequent signaling by chaperoning nascent G and facilitating heterodimer formation with G subunits (Lukov, G. L., Hu, T., McLaughlin, J. N., Hamm, H. E., and Willardson, B. M. (2005) EMBO J. 24, 1965-1975; Humrich, J., Bermel, C., Bunemann, M., Harmark, L., Frost, R., Quitterer, U., and Lohse, M. J. (2005) J. Biol. Chem. 280, 20042-20050). Here we demonstrate using a variety of techniques that DRiP78, an endoplasmic reticulum resident protein known to regulate the trafficking of several seven transmembrane receptors, interacts specifically with the G subunit but not G or G subunits. Furthermore, we demonstrate that DRiP78 and the G subunit can compete for the G subunit. DRiP78 also protects G from degradation until a stable partner such as G is provided. Furthermore, DRiP78 interaction may represent a mechanism for assembly of specific G heterodimers, as selectivity was observed among G isoforms for interaction with DRiP78 depending on the presence of particular G subunits. Interestingly, we could detect an interaction between DRiP78 and PhLP, suggesting a role of DRiP78 in the assembly of G by linking G to PhLP·G complexes. Our results, therefore, suggest a role of DRiP78 as a chaperone in the assembly of G subunits of the G protein.

Received for publication, September 13, 2006 , and in revised form, March 9, 2007.

^* This work was supported by grants from the Canadian Institutes of Health Research and Heart and Stroke Foundation of Quebec (to T. E. H.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-3.

¹ This author holds a postdoctoral fellowship from the Heart and Stroke Foundation of Canada.

² This author holds a senior scholarship from the Fonds de la Recherche en Santé du Québec. To whom correspondence should be addressed: Dept. of Pharmacology and Therapeutics, Faculty of Medicine, 13th floor, Rm. 1303, McIntyre Medical Sciences Bldg., 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada. Tel.: 514-398-1398; Fax: 514-398-6690; E-mail: terence.hebert{at}mcgill.ca.

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