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Vol. 15, Issue 11, 4926-4937, November 2004

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GIPC Recruits GAIP (RGS19) To Attenuate Dopamine D₂ Receptor Signaling

Freddy Jeanneteau ^* , Olivier Guillin ^*, Jorge Diaz , Nathalie Griffon ^*, and Pierre Sokoloff ^*

^* Unité de Neurobiologie et Pharmacologie Moléculaire Institut National de la Santé et de la Recherche Médicale U 573, Centre Paul Broca, 75104 Paris, France; Laboratoire de Physiologie, Faculté de Pharmacie, 75006 Paris, France

Submitted April 6, 2004; Revised July 29, 2004; Accepted August 16, 2004
Monitoring Editor: Suzanne Pfeffer

Pleiotropic G proteins are essential for the action of hormones and neurotransmitters and are activated by stimulation of G protein–coupled receptors (GPCR), which initiates heterotrimer dissociation of the G protein, exchange of GDP for GTP on its G subunit and activation of effector proteins. Regulator of G protein signaling (RGS) proteins regulate this cascade and can be recruited to the membrane upon GPCR activation. Direct functional interaction between RGS and GPCR has been hypothesized. We show that recruitment of GAIP (RGS19) by the dopamine D₂ receptor (D₂R), a GPCR, required the scaffold protein GIPC (GAIP-interacting protein, C terminus) and that all three were coexpressed in neurons and neuroendocrine cells. Dynamic translocation of GAIP to the plasma membrane and coassembly in a protein complex in which GIPC was a required component was dictated by D₂R activation and physical interactions. In addition, two different D₂R-mediated responses were regulated by the GTPase activity of GAIP at the level of the G protein coupling in a GIPC-dependent manner. Since GIPC exclusively interacted with GAIP and selectively with subsets of GPCR, this mechanism may serve to sort GPCR signaling in cells that usually express a large repertoire of GPCRs, G proteins, and RGS.

Abbreviations used: CHO, Chinese hamster ovary cells; Ct, C-terminus; D₂R, D₃R, and D₄R, dopamine D_2, D₃, and D₄ receptors; GAIP, Gi3-interacting protein; GIPC, GAIP-interacting protein C-terminus; GFP, green fluorescent protein; GPCR, G-protein–coupled receptor; GST, glutathione-S-transferase; HEK293, human embryonic kidney cells; ODN, oligodeoxynucleotide; PDZ, consensus sequence in PSD95/DLG/ZO-1; PM, plasma membrane; RGS, regulator of G-protein signaling.

The online version of this article contains supplementary material accessible at http://www.molbiolcell.org.

Corresponding author. E-mail address: jeannet{at}broca.inserm.fr.

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