G Protein-Coupled Receptor Kinase 2 Selectively Enhances β-Arrestin Recruitment to the D 2 Dopamine Receptor through Mechanisms That Are Independent of Receptor Phosphorylation.

Autor:	Sánchez-Soto, Marta, Boldizsar, Noelia M., Schardien, Kayla A., Madaras, Nora S., Willette, Blair K. A., Inbody, Laura R., Dasaro, Christopher, Moritz, Amy E., Drube, Julia, Haider, Raphael S., Free, R. Benjamin, Hoffman, Carsten, Sibley, David R.
Předmět:	ARRESTINS G protein coupled receptors DOPAMINE receptors REWARD (Psychology) PHOSPHORYLATION G proteins GENE expression
Zdroj:	Biomolecules (2218-273X); Oct2023, Vol. 13 Issue 10, p1552, 25p
Abstrakt:	The D2 dopamine receptor (D2R) signals through both G proteins and β-arrestins to regulate important physiological processes, such as movement, reward circuitry, emotion, and cognition. β-arrestins are believed to interact with G protein-coupled receptors (GPCRs) at the phosphorylated C-terminal tail or intracellular loops. GPCR kinases (GRKs) are the primary drivers of GPCR phosphorylation, and for many receptors, receptor phosphorylation is indispensable for β-arrestin recruitment. However, GRK-mediated receptor phosphorylation is not required for β-arrestin recruitment to the D2R, and the role of GRKs in D2R–β-arrestin interactions remains largely unexplored. In this study, we used GRK knockout cells engineered using CRISPR-Cas9 technology to determine the extent to which β-arrestin recruitment to the D2R is GRK-dependent. Genetic elimination of all GRK expression decreased, but did not eliminate, agonist-stimulated β-arrestin recruitment to the D2R or its subsequent internalization. However, these processes were rescued upon the re-introduction of various GRK isoforms in the cells with GRK2/3 also enhancing dopamine potency. Further, treatment with compound 101, a pharmacological inhibitor of GRK2/3 isoforms, decreased β-arrestin recruitment and receptor internalization, highlighting the importance of this GRK subfamily for D2R–β-arrestin interactions. These results were recapitulated using a phosphorylation-deficient D2R mutant, emphasizing that GRKs can enhance β-arrestin recruitment and activation independently of receptor phosphorylation. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
Externí odkaz:	Zobrazit plný text záznamu Plný text ve formátu HTML
Nepřihlášeným uživatelům se plný text nezobrazuje	K zobrazení výsledku je třeba se přihlásit.