G protein-coupled receptor kinases: more than just kinases and not only for GPCRs.
G protein-coupled receptor kinases: more than just kinases and not only for GPCRs.
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DOI：
10.1016/j.pharmthera.2011.08.001
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发表时间：
2012-01
影响因子：
13.5
通讯作者：
Gurevich, Vsevolod V.
中科院分区：
文献类型：
--
作者：
Gurevich, Eugenia V.;Tesmer, John J. G.;Mushegian, Arcady;Gurevich, Vsevolod V.
关键词：
G蛋白偶联受体(GPCRK)因其在GPCRs同源脱敏中的作用而广为人知。GRKs使激活的受体磷酸化，促进抑制素的高亲和力结合，从而阻止G蛋白偶联。GRK具有多结构域结构，其激活域被插入G蛋白信号同源结构域的调控环中。与许多其他的激酶不同，GRK不需要在其激活环中被磷酸化来达到激活状态。取而代之的是，它们通过与活动的GPCR对接直接激活。通过这种方式，它们能够选择性地磷酸化受体激活形式上的Ser/Thr残基，而不同于相关的蛋白激酶A。GRKs还可以磷酸化多种非GPCR底物，并以不依赖于磷酸化的方式与其他蛋白质直接相互作用来调节几个信号通路。几乎每个动物细胞中都存在多种GRK亚型，其中在神经元中的表达水平最高，其广泛而复杂的信号调节。GRK活性不足或过多与多种人类疾病有关，从心力衰竭到抑郁症再到帕金森氏症。作为GPCRs依赖和非依赖信号通路的关键调节因子，GRKs是新兴的药物靶点和有望用于治疗的分子工具。靶向调节几种GRK亚型的表达和/或活性用于治疗目的，最近在心脏疾病和帕金森病中得到验证。
G protein-coupled receptor (GPCR) kinases (GRKs) are best known for their role in homologous desensitization of GPCRs. GRKs phosphorylate activated receptors and promote high affinity binding of arrestins, which precludes G protein coupling. GRKs have a multidomain structure, with the kinase domain inserted into a loop of a regulator of G protein signaling homology domain. Unlike many other kinases, GRKs do not need to be phosphorylated in their activation loop to achieve an activated state. Instead, they are directly activated by docking with active GPCRs. In this manner they are able to selectively phosphorylate Ser/Thr residues on only the activated form of the receptor, unlike related kinases such as protein kinase A. GRKs also phosphorylate a variety of non-GPCR substrates and regulate several signaling pathways via direct interactions with other proteins in a phosphorylation-independent manner. Multiple GRK subtypes are present in virtually every animal cell, with the highest expression levels found in neurons, with their extensive and complex signal regulation. Insufficient or excessive GRK activity was implicated in a variety of human disorders, ranging from heart failure to depression to Parkinson’s disease. As key regulators of GPCR-dependent and -independent signaling pathways, GRKs are emerging drug targets and promising molecular tools for therapy. Targeted modulation of expression and/or of activity of several GRK isoforms for therapeutic purposes was recently validated in cardiac disorders and Parkinson’s disease.
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影响因子：
4.8
作者：
Bayburt, Timothy H.;Vishnivetskiy, Sergey A.;Gurevich, Vsevolod V.
通讯作者：
Gurevich, Vsevolod V.
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.95.6.2985
发表时间：
1998-03-17
影响因子：
11.1
作者：
Aragay, AM;Mellado, M;Mayor, F
通讯作者：
Mayor, F
影响因子：
11
作者：
Barrett, TB;Hauger, RL;Kelsoe, JR
通讯作者：
Kelsoe, JR
影响因子：
3.5
作者：
Ambrose, Christine;James, Marianne;Church, Deanne
通讯作者：
Church, Deanne