G protein-coupled receptor kinases as regulators of dopamine receptor functions.
G protein-coupled receptor kinases as regulators of dopamine receptor functions.
复制标题
G蛋白偶联受体激酶是多巴胺受体功能的调节剂。
DOI：
10.1016/j.phrs.2016.05.010
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发表时间：
2016-09
影响因子：
9.3
通讯作者：
Gurevich, Vsevolod V.
中科院分区：
文献类型：
--
作者：
Gurevich, Eugenia V.;Gainetdinov, Raul R.;Gurevich, Vsevolod V.
关键词：
神经递质多巴胺在大脑中的作用由属于G蛋白偶联受体（GPCR）超家族的多巴胺受体介导。哺乳动物有五种多巴胺受体亚型，D1至D5。D1和D5与Gs/olf偶联并激活腺苷酸环化酶，而D2、D3和D4与Gi/o偶联并抑制它。GRK磷酸化使受体成为抑制蛋白的高亲和力结合伴侣。抑制蛋白与活性磷酸化受体的结合阻止了G蛋白的进一步活化，并促进受体的内化、再循环或降解，从而调节它们的信号传导和运输。四种非视觉GRKs在纹状体神经元中表达。在这里，我们描述了已知的影响，个别GRKs对多巴胺受体的细胞培养和多巴胺介导的信号传导的两个体内模型：行为反应的精神兴奋剂和左旋多巴诱导的运动障碍。与纹状体神经元的多巴胺超敏感性相关的运动障碍是左旋多巴治疗帕金森病的一种使人衰弱的副作用。在体内，GRK亚型显示出比体外或培养细胞更大的受体特异性。过表达，敲低，敲除个别GRKs，特别是GRK 2和GRK 6，有不同的影响信号的多巴胺受体亚型在大脑中。此外，删除GRK亚型在选择纹状体神经元类型的差异影响精神兴奋剂诱导的行为。此外，GRK 3的抗运动障碍作用不需要其激酶活性：它是通过其RGS-like结构域与Gαq/11的结合介导的，这抑制了Gq/11信号传导。这些数据表明，多巴胺信号在体内定义的神经元类型是由特定的和精细的协调行动的GRK亚型。
Actions of the neurotransmitter dopamine in the brain are mediated by dopamine receptors that belong to the superfamily of G protein-coupled receptors (GPCRs). Mammals have five dopamine receptor subtypes, D1 through D5. D1 and D5 couple to Gs/olf and activate adenylyl cyclase, whereas D2, D3, and D4 couple to Gi/o and inhibit it. Most GPCRs upon activation by an agonist are phosphorylated by GPCR kinases (GRKs). The GRK phosphorylation makes receptors high-affinity binding partners for arrestin proteins. Arrestin binding to active phosphorylated receptors stops further G protein activation and promotes receptor internalization, recycling or degradation, thereby regulating their signaling and trafficking. Four non-visual GRKs are expressed in striatal neurons. Here we describe known effects of individual GRKs on dopamine receptors in cell culture and in the two in vivo models of dopamine-mediated signaling: behavioral response to psychostimulants and L-DOPA-induced dyskinesia. Dyskinesia, associated with dopamine super-sensitivity of striatal neurons, is a debilitating side effect of L-DOPA therapy in Parkinson’s disease. In vivo, GRK subtypes show greater receptor specificity than in vitro or in cultured cells. Overexpression, knockdown, and knockout of individual GRKs, particularly GRK2 and GRK6, have differential effects on signaling of dopamine receptor subtypes in the brain. Furthermore, deletion of GRK isoforms in select striatal neuronal types differentially affects psychostimulant-induced behaviors. In addition, anti-dyskinetic effect of GRK3 does not require its kinase activity: it is mediated by the binding of its RGS-like domain to Gαq/11, which suppresses Gq/11 signaling. The data demonstrate that the dopamine signaling in defined neuronal types in vivo is regulated by specific and finely orchestrated actions of GRK isoforms.
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影响因子：
6.1
作者：
Bezard, E;Gross, CE;Gurevich, EV
通讯作者：
Gurevich, EV
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：
56.9
作者：
Bohn, LM;Lefkowitz, RJ;Lin, FT
通讯作者：
Lin, FT
影响因子：
82.9
作者：
Bézard, E;Ferry, S;Sokoloff, P
通讯作者：
Sokoloff, P
影响因子：
4.6
作者：
Ahmed MR;Bychkov E;Li L;Gurevich VV;Gurevich EV
通讯作者：
Gurevich EV