Han Chen-Chen, Ma Yang, Li Yifan, Wang Yang, Wei Wei
Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui 230032, P.R. China.
Int J Mol Med. 2016 Oct;38(4):987-94. doi: 10.3892/ijmm.2016.2720. Epub 2016 Aug 29.
G protein-coupled receptor kinase 2 (GRK2) is a key member of the G protein-coupled receptor kinase (GRK) family. GRK2 activity is regulated by the C-terminus of GRK2 which contains a plekstrin homology domain and the N-terminus of GRK2 which contains the RGS homology domain with binding sites for several proteins and lipids such as G protein-coupled receptors (GPCRs), G protein, phospholipase C, phosphatidylinositol 4,5-bisphosphate, extracellular signal‑regulated kinase, protein kinase A and Gβγ. GRK2 phosphorylates the GPCR and enhances the affinity of binding to arrestins, which uncouple the receptors from G proteins, and target the receptors for desensitization and internalization. GRK2 also regulates non‑GPCR desensitization and internalization by phosphorylation, and is important in maintaining the balance between the receptors and signal transduction. Previous findings have indicated that the upregulation of GRK2 in heart failure enhances dysfunctional adrenergic signaling and myocyte death. Collagen-induced arthritis induces the upregulation of GRK2 expression in fibroblast-like synoviocytes. In this review, we discussed the evidence for the association between altered GRK2 levels and various diseases, which suggests that GRK2 may be an effective drug target for preventing and treating heart failure, hypertension and inflammatory disease.
G蛋白偶联受体激酶2（GRK2）是G蛋白偶联受体激酶（GRK）家族的关键成员。GRK2的活性受其C末端（包含一个普列克底物蛋白同源结构域）和N末端（包含RGS同源结构域，具有与几种蛋白质和脂质的结合位点，如G蛋白偶联受体（GPCRs）、G蛋白、磷脂酶C、磷脂酰肌醇4,5-二磷酸、细胞外信号调节激酶、蛋白激酶A和Gβγ）的调节。GRK2使GPCR磷酸化，并增强其与阻遏蛋白的结合亲和力，从而使受体与G蛋白解偶联，并促使受体脱敏和内化。GRK2还通过磷酸化调节非GPCR的脱敏和内化，在维持受体与信号转导之间的平衡中起重要作用。先前的研究结果表明，心力衰竭中GRK2的上调会增强功能失调的肾上腺素能信号传导和心肌细胞死亡。胶原诱导的关节炎会诱导成纤维样滑膜细胞中GRK2表达上调。在本综述中，我们讨论了GRK2水平改变与各种疾病之间关联的证据，这表明GRK2可能是预防和治疗心力衰竭、高血压和炎症性疾病的有效药物靶点。
