Molecular mechanism of desensitization of the chemokine receptor CCR-5: receptor signaling and internalization are dissociable from its role as an HIV-1 co-receptor
Molecular mechanism of desensitization of the chemokine receptor CCR-5: receptor signaling and internalization are dissociable from its role as an HIV-1 co-receptor
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DOI：
10.1093/emboj/16.15.4606
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发表时间：
1997-08-01
期刊：
影响因子：
11.4
通讯作者：
Caron, MG
中科院分区：
文献类型：
--
作者：
Aramori, I;Zhang, J;Caron, MG
趋化因子受体CCR-5是介导某些白细胞趋化反应的G蛋白偶联受体，是巨噬细胞嗜人免疫缺陷病毒1型(HIV-1)的主要共受体。本文描述了CCR-5通过百日咳毒素敏感的G(I)蛋白机制，在HEK 293细胞中通过百日咳毒素敏感的G(I)蛋白机制抑制Forsklin刺激的cAMP形成的功能偶联。在趋化因子的反应下，CCR-5只有在HEK 293细胞中过表达G蛋白受体偶联蛋白(GRKs)和β-arrestins后，才被脱敏、磷酸化和隔离。在没有GRK过表达的HEK 293细胞中，CCR-5缺乏脱敏作用，这表明GRK和/或β-arrestin蛋白在细胞补体中的差异可能是决定细胞反应性的一个重要机制。当测试时，CCR-5作为HIV-1共受体的活性既不依赖于其信号传递能力，也不依赖于其在激动剂刺激后脱敏和内化的能力，因此，虽然趋化因子促进细胞信号转导，CCR-5的磷酸化和内化可能在调节白细胞的趋化反应中发挥重要作用，但这些功能与其HIV-1共受体功能是分离的。
The chemokine receptor, CCR-5, a G protein-coupled receptor (GPCR) which mediates chemotactic responses of certain leukocytes, has been shown to serve as the primary co-receptor for macrophage-tropic human immunodeficiency virus type 1 (HIV-1), Here vee describe functional coupling of CCR-5 to inhibition of forskolin-stimulated cAMP formation via pertussis toxin-sensitive G(i) protein mechanism in transfected HEK 293 cells, In response to chemokines, CCR-5 was desensitized, phosphorylated and sequestered like a prototypic GPCR only following overexpression of G protein-coupled receptor kinases (GRKs) and beta-arrestins in HEK 293 cells, The lack of CCR-5 desensitization in HEK 293 cells in the absence of GRK overexpression suggests that differences in cellular complements of GRK and/or beta-arrestin proteins could represent an important mechanism determining cellular responsiveness, When tested, the activity of CCR-5 as an HIV-1 co-receptor was dependent neither upon its ability to signal nor its ability to be desensitized and internalized following agonist stimulation, Thus, while chemokine-promoted cellular signaling, phosphorylation and internalization of CCR-5 may play an important role in regulation of chemotactic responses in leukocytes, these functions are dissociable from its HIV-1 co-receptor function.