GPCR desensitization: Acute and prolonged phases.
GPCR desensitization: Acute and prolonged phases.
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DOI：
10.1016/j.cellsig.2017.01.024
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发表时间：
2018-01
影响因子：
4.8
通讯作者：
Shenoy SK
中科院分区：
文献类型：
--
作者：
Rajagopal S;Shenoy SK
G 蛋白偶联受体 (GPCR) 转导多种细胞外信号并调节生理学的几乎各个方面。虽然 GPCR 信号传导至关重要，但过度刺激可能是有害的，导致细胞毒性或不受控制的细胞生长。因此，大自然已经开发出许多限制GPCR信号传导的机制，这些机制广泛地称为脱敏，是指对重复或连续刺激的反应减少。短期脱敏发生在几分钟内，主要与阻止 G 蛋白与 GPCR 相互作用的 β-抑制蛋白有关。长期脱敏（称为下调）会发生数小时至数天，涉及受体内化到囊泡中、溶酶体降解以及通过不清楚的机制降低受体 mRNA 水平。 GPCR 激酶（GRK）对受体的磷酸化和 β-抑制蛋白的募集对于这些短期和长期脱敏机制至关重要。除了磷酸化之外，GPCR 和 β-arrestin 还以多种方式进行翻译后修饰，包括泛素化。对于许多 GPCR，受体泛素化会促进溶酶体中激动剂激活的受体的降解。其他蛋白质在脱敏中也发挥着重要作用，包括磷酸二酯酶、RGS 家族蛋白和 A-激酶锚定蛋白。这个由激酶、泛素连接酶和接头蛋白组成的复杂网络共同协调 GPCR 的急性和长期脱敏。
G protein-coupled receptors (GPCRs) transduce a wide array of extracellular signals and regulate virtually every aspect of physiology. While GPCR signaling is essential, overstimulation can be deleterious, resulting in cellular toxicity or uncontrolled cellular growth. Accordingly, nature has developed a number of mechanisms for limiting GPCR signaling, which are broadly referred to as desensitization, and refer to a decrease in response to repeated or continuous stimulation. Short-term desensitization occurs over minutes, and is primarily associated with β-arrestins preventing G protein interaction with a GPCR. Longer-term desensitization, referred to as downregulation, occurs over hours to days, and involves receptor internalization into vesicles, degradation in lysosomes and decreased receptor mRNA levels through unclear mechanisms. Phosphorylation of the receptor by GPCR kinases (GRKs) and the recruitment of β-arrestins is critical to both these short- and long-term desensitization mechanisms. In addition to phosphorylation, both the GPCR and β-arrestins are modified post-translationally in several ways, including by ubiquitination. For many GPCRs, receptor ubiquitination promotes degradation of agonist-activated receptors in the lysosomes. Other proteins also play important roles in desensitization, including phosphodiesterases, RGS family proteins and A-kinase-anchoring proteins. Together, this intricate network of kinases, ubiquitin ligases, and adaptor proteins orchestrate the acute and prolonged desensitization of GPCRs.
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DOI：
10.1073/pnas.84.24.8879
发表时间：
1987-12-01
影响因子：
11.1
作者：
BENOVIC, JL;KUHN, H;LEFKOWITZ, RJ
通讯作者：
LEFKOWITZ, RJ
DOI：
10.1073/pnas.83.9.2797
发表时间：
1986-05-01
影响因子：
11.1
作者：
BENOVIC, JL;STRASSER, RH;LEFKOWITZ, RJ
通讯作者：
LEFKOWITZ, RJ
影响因子：
64.8
作者：
Goodman, OB;Krupnick, JG;Benovic, JL
通讯作者：
Benovic, JL
影响因子：
14.8
作者：
Ferrandon, Sebastien;Feinstein, Timothy N.;Castro, Marian;Wang, Bin;Bouley, Richard;Potts, John T.;Gardella, Thomas J.;Vilardaga, Jean-Pierre
通讯作者：
Vilardaga, Jean-Pierre
影响因子：
3.6
作者：
Gimenez, Luis E.;Baameur, Faiza;Clark, Richard B.
通讯作者：
Clark, Richard B.