title: β-arrestin2 plays permissive roles in the inhibitory activities of RGS9-2 on G protein-coupled receptors by maintaining RGS9-2 in the open conformation.
abstract: Together with G protein-coupled receptor (GPCR) kinases (GRKs) and β-arrestins, RGS proteins are the major family of molecules that control the signaling of GPCRs. The expression pattern of one of these RGS family members, RGS9-2, coincides with that of the dopamine D(3) receptor (D(3)R) in the brain, and in vivo studies have shown that RGS9-2 regulates the signaling of D2-like receptors. In this study, β-arrestin2 was found to be required for scaffolding of the intricate interactions among the dishevelled-EGL10-pleckstrin (DEP) domain of RGS9-2, Gβ5, R7-binding protein (R7BP), and D(3)R. The DEP domain of RGS9-2, under the permission of β-arrestin2, inhibited the signaling of D(3)R in collaboration with Gβ5. β-Arrestin2 competed with R7BP and Gβ5 so that RGS9-2 is placed in the cytosolic region in an open conformation which is able to inhibit the signaling of GPCRs. The affinity of the receptor protein for β-arrestin2 was a critical factor that determined the selectivity of RGS9-2 for the receptor it regulates. These results show that β-arrestins function not only as mediators of receptor-G protein uncoupling and initiators of receptor endocytosis but also as scaffolding proteins that control and coordinate the inhibitory effects of RGS proteins on the signaling of certain GPCRs.
authors: Department of Pharmacology, College of Pharmacy, Chonnam National University, Gwang-Ju 500-757, South Korea.
authors: Mei
authors: M
authors: Zheng
authors: Sang-Yoon
authors: SY
authors: Cheong
authors: Chengchun
authors: C
authors: Min
authors: Mingli
authors: M
authors: Jin
authors: Dong-Im
authors: DI
authors: Cho
authors: Kyeong-Man
authors: KM
authors: Kim
mesh_terms: D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D004705:Endocytosis; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D010957:Plasmids; D020710:RGS Proteins / Q000235:genetics* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000235:genetics*; D015398:Signal Transduction; D014162:Transfection / Q000379:methods; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; C499440:R7BP protein, mouse; D020710:RGS Proteins; D034741:RNA, Small Interfering; D050637:Receptors, Dopamine D3; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; C116925:regulator of g-protein signaling 9