期刊
MOLECULAR ENDOCRINOLOGY
卷 24, 期 3, 页码 574-586出版社
ENDOCRINE SOC
DOI: 10.1210/me.2009-0369
关键词
-
资金
- Korean Research Foundation [KRF-2007-E00629]
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- National Institutes of Health [MH-66197]
- National Science Foundation [IBN-0133538]
The regulatory mechanisms and functional roles of agonist-induced internalization of G protein-coupled receptors (GPCRs) were analyzed using mutant dopamine D-2 receptors (D(2)Rs) in which all possible GPCR kinase (GRK) phosphorylation sites were mutated or the affinity for beta-arrestins was altered. Agonist-induced internalization of D(2)Rs involved a phosphorylation-dependent component, which was mediated by serine/threonine (S/T) residues in the second loop and T225 in the third loop, and a phosphorylation-independent component. GRK2-mediated enhancement of the internalization and inhibition of D2R signaling did not involve receptor phosphorylation, and only the former required the enzymatic activity of GRK2. The phosphorylation-deficient mutant (D2R-intracellular loop 2/3) recycled more slowly and showed more agonist-induced desensitization than did the wild-type D2R, suggesting that receptor phosphorylation mediates the recycling of the internalized receptors and enhances receptor resensitization. Blockade of the agonist-induced internalization of D2R-intracellular loop 2/3 provoked desensitization as in wild-type D2R, suggesting that certain cellular processes other than receptor dephosphorylation occurring within the endocytic vesicle are responsible for the resensitization of D2R. When dissociation between D2R and beta-arrestin was inhibited or when the expression of cellular beta-arrestins was decreased, agonist-induced desensitization of D2R did not occur, suggesting that dissociation from beta-arrestin is the main cellular process required for resensitization of D2R and is achieved through agonist-induced internalization. These results indicate that, in the regulation of some GPCRs, phosphorylation-independent association with beta-arrestin plays a major role in agonist-induced desensitization. (Molecular Endocrinology 24: 574-586, 2010)
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据