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Vol. 15, Issue 2, 696-705, February 2004
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* Unité de Neurobiologie et Pharmacologie Moléculaire INSERM U 573, Centre Paul Broca, 75014 Paris, France;
Laboratoire de Physiologie, Faculté de Pharmacie, 75006 Paris, France
Submitted May 13, 2003;
Revised September 30, 2003;
Accepted September 30, 2003
Monitoring Editor: Suzanne Pfeffer
The C-terminus domain of G protein-coupled receptors confers a functional cytoplasmic interface involved in protein association. By screening a rat brain cDNA library using the yeast two-hybrid system with the C-terminus domain of the dopamine D3 receptor (D3R) as bait, we characterized a new interaction with the PDZ domain-containing protein, GIPC (GAIP interacting protein, C terminus). This interaction was specific for the dopamine D2 receptor (D2R) and D3R, but not for the dopamine D4 receptor (D4R) subtype. Pull-down and affinity chromatography assays confirmed this interaction with recombinant and endogenous proteins. Both GIPC mRNA and protein are widely expressed in rat brain and together with the D3R in neurons of the islands of Calleja at plasma membranes and in vesicles. GIPC reduced D3R signaling, cointernalized with D2R and D3R, and sequestered receptors in sorting vesicles to prevent their lysosomal degradation. Through its dimerization, GIPC acts as a selective scaffold protein to assist receptor functions. Our results suggest a novel function for GIPC in the maintenance, trafficking, and signaling of GPCRs.
Abbreviations used: aa, amino acids; Ct, C-terminus; D2R, D3R and D4R, dopamine D2, D3, and D4 receptors; GAIP, G
i3 interacting protein; GIPC, GAIP-interacting protein C-terminus; GFP, green fluorescent protein; GPCR, G protein-coupled receptor; GRK, G protein-coupled receptor kinase; GST, glutathione S-transferase; HEK293, embrionic kidney cells; PDZ, consensus sequence in PSD95/DLG/zo-1; RGS, regulator of G protein signaling.
Corresponding author. E-mail address: jeannet{at}broca.inserm.fr or sokol{at}broca.inserm.fr.
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