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J. Biol. Chem., Vol. 282, Issue 26, 19203-19216, June 29, 2007

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Signaling through a G Protein-coupled Receptor and Its Corresponding G Protein Follows a Stoichiometrically Limited Model^*

From the Department of Physiology and Biophysics, Stony Brook University Medical Center, Stony Brook, New York 11794-8661

The bradykinin receptor is a G protein-coupled receptor (GPCR) that is coupled to the G_q family of heterotrimeric G proteins. In general, a GPCR can exert intracellular signals either by transiently associating with multiple diffusing G protein subunits or by activating a G protein that is stably bound to the receptor, thus generating a signal that is limited by the stoichiometry of the complex. Here we have distinguished between these models by monitoring the association of type 2 bradykinin receptor (B₂R) and the G_q/G heterotrimer in living human embryonic kidney 293 cells expressing fluorescent-tagged proteins. Stable B₂R-G_q·G complexes are observed in resting cells by fluorescence resonance energy transfer from either G_q-eCFP or eCFP-G to B₂R-eYFP. Stimulating the cells with bradykinin causes detachment of B₂R from the G protein subunits as the receptor internalizes into early endosomes, with a corresponding elimination of B₂R-G protein fluorescence resonance energy transfer because G_q and its associated G remain on the plasma membrane. Single point and scanning fluorescence correlation spectroscopy measurements show that a portion of B₂R molecules diffuses with a mobility corresponding to dimers or small oligomers, whereas a second fraction diffuses in higher order molecular assemblies. Our studies support a model in which receptors are pre-coupled with their corresponding G proteins in the basal state of cells thereby limiting the response to an external signal to a defined stoichiometry that allows for a rapid and directed cellular response.

Received for publication, February 21, 2007 , and in revised form, April 4, 2007.

^* This work was supported by National Institutes of Health Grant GM53132. 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 To whom correspondence should be addressed. Tel.: 631-444-3071; Fax: 631-444-3432; E-mail: Suzanne.Scarlata{at}sunysb.edu.

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