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• W2085392760 endingPage "123" @default.
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• W2085392760 abstract "Arrestins mediate G protein-coupled receptor desensitization, internalization, and signaling. Dopamine D₂ and D₃ receptors have similar structures but distinct characteristics of interaction with arrestins. The goals of this study were to compare arrestin-binding determinants in D₂ and D₃ receptors other than phosphorylation sites and to create a D₂ receptor that is deficient in arrestin binding. We first assessed the ability of purified arrestins to bind to glutathione transferase (GST) fusion proteins containing the receptor third intracellular loops (IC3). Arrestin3 bound to IC3 of both D₂ and D₃ receptors, with the affinity and localization of the binding site indistinguishable between the receptor subtypes. Mutagenesis of the GST-IC3 fusion proteins identified an important determinant of the binding of arrestin3 in the N-terminal region of IC3. Alanine mutations of this determinant (IYIV212-215) in the full-length D₂ receptor generated a signaling-biased receptor with intact ligand binding and G-protein coupling and activation, but deficient in receptor-mediated arrestin3 translocation to the membrane, agonist-induced receptor internalization, and agonist-induced desensitization in human embryonic kidney 293 cells. This mutation also decreased arrestin-dependent activation of extracellular signal-regulated kinases. The finding that nonphosphorylated D₂-IC3 and D₃-IC3 have similar affinity for arrestin is consistent with previous suggestions that the differential effects of D₂ and D₃ receptor activation on membrane translocation of arrestin and receptor internalization are due, at least in part, to differential phosphorylation of the receptors. In addition, these results imply that the sequence IYIV212-215 at the N terminus of IC3 of the D₂ receptor is a key element of the arrestin binding site." @default.
• W2085392760 created "2016-06-24" @default.
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• W2085392760 date "2008-09-22" @default.
• W2085392760 modified "2023-09-27" @default.
• W2085392760 title "A Dopamine D₂Receptor Mutant Capable of G Protein-Mediated Signaling but Deficient in Arrestin Binding" @default.
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• W2085392760 doi "https://doi.org/10.1124/mol.108.050534" @default.
• W2085392760 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2606918" @default.
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