将G蛋白偶联受体激酶（GRKs）靶向作用于G蛋白偶联受体。
Targeting G protein-coupled receptor kinases (GRKs) to G protein-coupled receptors.
作者信息
Sulon Sarah M, Benovic Jeffrey L
机构信息
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
出版信息
Curr Opin Endocr Metab Res. 2021 Feb;16:56-65. doi: 10.1016/j.coemr.2020.09.002. Epub 2020 Sep 18.
Abstract
G protein-coupled receptors (GPCRs) interact with three protein families following agonist binding: heterotrimeric G proteins, G protein-coupled receptor kinases (GRKs) and arrestins. GRK-mediated phosphorylation of GPCRs promotes arrestin binding to uncouple the receptor from G protein, a process called desensitization, and for many GPCRs, arrestin binding also promotes receptor endocytosis and intracellular signaling. Thus, GRKs play a central role in modulating GPCR signaling and localization. Here we review recent advances in this field which include additional insight into how GRKs target GPCRs and bias signaling, and the development of specific inhibitors to dissect GRK function in model systems.
摘要
G蛋白偶联受体（GPCRs）在激动剂结合后与三个蛋白家族相互作用：异源三聚体G蛋白、G蛋白偶联受体激酶（GRKs）和抑制蛋白。GRK介导的GPCR磷酸化促进抑制蛋白结合，使受体与G蛋白解偶联，这一过程称为脱敏，对于许多GPCR来说，抑制蛋白结合还促进受体内吞作用和细胞内信号传导。因此，GRKs在调节GPCR信号传导和定位中起核心作用。在此，我们综述该领域的最新进展，包括对GRKs如何靶向GPCRs和偏向信号传导的更多见解，以及在模型系统中剖析GRK功能的特异性抑制剂的开发。
相似文献
1
Targeting G protein-coupled receptor kinases (GRKs) to G protein-coupled receptors.将G蛋白偶联受体激酶（GRKs）靶向作用于G蛋白偶联受体。
Curr Opin Endocr Metab Res. 2021 Feb;16:56-65. doi: 10.1016/j.coemr.2020.09.002. Epub 2020 Sep 18.
2
Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling.G蛋白偶联受体内吞作用的演变概念：在受体脱敏和信号传导中的作用。
Pharmacol Rev. 2001 Mar;53(1):1-24.
3
Multiple functions of G protein-coupled receptor kinases.G蛋白偶联受体激酶的多种功能。
J Mol Signal. 2014 Mar 6;9(1):1. doi: 10.1186/1750-2187-9-1.
4
G protein-coupled receptor interactions with arrestins and GPCR kinases: The unresolved issue of signal bias.G 蛋白偶联受体与阻滞蛋白和 GPCR 激酶的相互作用：信号偏向的未解决问题。
J Biol Chem. 2022 Sep;298(9):102279. doi: 10.1016/j.jbc.2022.102279. Epub 2022 Jul 19.
5
G-protein-coupled receptor regulation: role of G-protein-coupled receptor kinases and arrestins.G蛋白偶联受体的调控：G蛋白偶联受体激酶和抑制蛋白的作用
Can J Physiol Pharmacol. 1996 Oct;74(10):1095-110. doi: 10.1139/cjpp-74-10-1095.
6
GPCR Signaling Regulation: The Role of GRKs and Arrestins.G蛋白偶联受体信号转导调控：G蛋白偶联受体激酶和抑制蛋白的作用
Front Pharmacol. 2019 Feb 19;10:125. doi: 10.3389/fphar.2019.00125. eCollection 2019.
7
Once and future signaling: G protein-coupled receptor kinase control of neuronal sensitivity.既往与未来的信号传导：G蛋白偶联受体激酶对神经元敏感性的调控
Neuromolecular Med. 2005;7(1-2):129-47. doi: 10.1385/NMM:7:1-2:129.
8
Desensitization of G protein-coupled receptors.G蛋白偶联受体的脱敏作用。
Recent Prog Horm Res. 1996;51:319-51; discussion 352-3.
9
G Protein-coupled Receptor Kinases of the GRK4 Protein Subfamily Phosphorylate Inactive G Protein-coupled Receptors (GPCRs).GRK4蛋白亚家族的G蛋白偶联受体激酶使无活性的G蛋白偶联受体（GPCRs）磷酸化。
J Biol Chem. 2015 Apr 24;290(17):10775-90. doi: 10.1074/jbc.M115.644773. Epub 2015 Mar 13.
10
GRKs as Modulators of Neurotransmitter Receptors.G 蛋白偶联受体激酶作为神经递质受体的调节剂。
Cells. 2020 Dec 31;10(1):52. doi: 10.3390/cells10010052.
引用本文的文献
1
Genetic variants of accessory proteins and G proteins in human genetic disease.人类遗传疾病中辅助蛋白和G蛋白的基因变异
Crit Rev Clin Lab Sci. 2025 Mar;62(2):113-134. doi: 10.1080/10408363.2024.2431853. Epub 2025 Jan 1.
2
G protein-coupled receptor kinases in hypertension: physiology, pathogenesis, and therapeutic targets.G 蛋白偶联受体激酶在高血压中的作用：生理、发病机制和治疗靶点。
Hypertens Res. 2024 Sep;47(9):2317-2336. doi: 10.1038/s41440-024-01763-y. Epub 2024 Jul 3.
3
Exploiting Cell-Based Assays to Accelerate Drug Development for G Protein-Coupled Receptors.利用基于细胞的 assays 加速 G 蛋白偶联受体的药物开发。
Int J Mol Sci. 2024 May 17;25(10):5474. doi: 10.3390/ijms25105474.
4
Differential Modulation of Catecholamine and Adipokine Secretion by the Short Chain Fatty Acid Receptor FFAR3 and α-Adrenergic Receptors in PC12 Cells.短链脂肪酸受体 FFAR3 和 α-肾上腺素能受体对 PC12 细胞儿茶酚胺和脂肪因子分泌的差异调节。
Int J Mol Sci. 2024 May 11;25(10):5227. doi: 10.3390/ijms25105227.
5
Structure, function and drug discovery of GPCR signaling.G蛋白偶联受体（GPCR）信号传导的结构、功能与药物发现
Mol Biomed. 2023 Dec 4;4(1):46. doi: 10.1186/s43556-023-00156-w.
6
Development of a new class of potent and highly selective G protein-coupled receptor kinase 5 inhibitors and structural insight from crystal structures of inhibitor complexes.新型强效高选择性 G 蛋白偶联受体激酶 5 抑制剂的开发及其抑制剂复合物晶体结构的结构见解。
Eur J Med Chem. 2024 Jan 15;264:115931. doi: 10.1016/j.ejmech.2023.115931. Epub 2023 Nov 10.
7
GPCR activation and GRK2 assembly by a biased intracellular agonist.G 蛋白偶联受体的激活和 GRK2 组装由偏向性细胞内激动剂介导。
Nature. 2023 Aug;620(7974):676-681. doi: 10.1038/s41586-023-06395-9. Epub 2023 Aug 2.
8
Control of Gα signaling dynamics and GPCR cross-talk by GRKs.GRK对Gα信号动力学和GPCR相互作用的调控
Sci Adv. 2022 Nov 25;8(47):eabq3363. doi: 10.1126/sciadv.abq3363.
9
Selective phosphorylation of threonine residues defines GPR84-arrestin interactions of biased ligands.选择性磷酸化苏氨酸残基定义了偏向配体与 GPR84-衔接蛋白的相互作用。
J Biol Chem. 2022 May;298(5):101932. doi: 10.1016/j.jbc.2022.101932. Epub 2022 Apr 12.
10
Serotonin Receptor and Transporter Endocytosis Is an Important Factor in the Cellular Basis of Depression and Anxiety.血清素受体与转运体的内吞作用是抑郁和焦虑细胞基础中的一个重要因素。
Front Cell Neurosci. 2022 Feb 24;15:804592. doi: 10.3389/fncel.2021.804592. eCollection 2021.
本文引用的文献
1
Biased GPCR signaling: Possible mechanisms and inherent limitations.偏向性 G 蛋白偶联受体信号转导：可能的机制与固有局限
Pharmacol Ther. 2020 Jul;211:107540. doi: 10.1016/j.pharmthera.2020.107540. Epub 2020 Mar 19.
2
Phosphorylation at Serine 21 in G protein-coupled receptor kinase 1 (GRK1) is required for normal kinetics of dark adaption in rod but not cone photoreceptors.丝氨酸 21 位的磷酸化是 G 蛋白偶联受体激酶 1（GRK1）在暗适应正常动力学中必需的，但其在视杆细胞而不是视锥细胞中起作用。
FASEB J. 2020 Feb;34(2):2677-2690. doi: 10.1096/fj.201902535R. Epub 2019 Dec 30.
3
Structure-Based Design of Selective, Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors.基于结构的选择性共价G蛋白偶联受体激酶5抑制剂设计
ACS Med Chem Lett. 2019 Nov 12;10(12):1628-1634. doi: 10.1021/acsmedchemlett.9b00365. eCollection 2019 Dec 12.
4
Perturbation of the interactions of calmodulin with GRK5 using a natural product chemical probe.利用天然产物化学探针干扰钙调蛋白与 GRK5 的相互作用。
Proc Natl Acad Sci U S A. 2019 Aug 6;116(32):15895-15900. doi: 10.1073/pnas.1818547116. Epub 2019 Jul 23.
5
The COMMD3/8 complex determines GRK6 specificity for chemoattractant receptors.COMMD3/8 复合物决定了趋化因子受体中 GRK6 的特异性。
J Exp Med. 2019 Jul 1;216(7):1630-1647. doi: 10.1084/jem.20181494. Epub 2019 May 14.
6
Distinct G protein-coupled receptor phosphorylation motifs modulate arrestin affinity and activation and global conformation.不同的 G 蛋白偶联受体磷酸化基序调节阻滞蛋白的亲和力和激活以及整体构象。
Nat Commun. 2019 Mar 19;10(1):1261. doi: 10.1038/s41467-019-09204-y.
7
GPCR Signaling Regulation: The Role of GRKs and Arrestins.G蛋白偶联受体信号转导调控：G蛋白偶联受体激酶和抑制蛋白的作用
Front Pharmacol. 2019 Feb 19;10:125. doi: 10.3389/fphar.2019.00125. eCollection 2019.
8
Sensitization of the Angiotensin II AT1 Receptor Contributes to RKIP-Induced Symptoms of Heart Failure.血管紧张素II 1型受体的致敏作用促成了RKIP诱导的心力衰竭症状。
Front Med (Lausanne). 2019 Jan 9;5:359. doi: 10.3389/fmed.2018.00359. eCollection 2018.
9
G protein-coupled receptor kinases (GRKs) orchestrate biased agonism at the β-adrenergic receptor.G 蛋白偶联受体激酶（GRKs）在β肾上腺素能受体处协调偏激动作用。
Sci Signal. 2018 Aug 21;11(544):eaar7084. doi: 10.1126/scisignal.aar7084.
10
GRK2 mediates TCR-induced transactivation of CXCR4 and TCR-CXCR4 complex formation that drives PI3Kγ/PREX1 signaling and T cell cytokine secretion.GRK2 介导 TCR 诱导的 CXCR4 转激活和 TCR-CXCR4 复合物形成，从而驱动 PI3Kγ/PREX1 信号和 T 细胞细胞因子分泌。
J Biol Chem. 2018 Sep 7;293(36):14022-14039. doi: 10.1074/jbc.RA118.003097. Epub 2018 Jul 17.
Zotero 插件