Roles of subunit phosphorylation in regulating glutamate receptor function.
Roles of subunit phosphorylation in regulating glutamate receptor function.
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DOI：
10.1016/j.ejphar.2013.11.019
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发表时间：
2014-04-05
影响因子：
5
通讯作者：
Mao, Li-Min
中科院分区：
文献类型：
--
作者：
Wang, John Q.;Guo, Ming-Lei;Jin, Dao-Zhong;Xue, Bing;Fibuch, Eugene E.;Mao, Li-Min
蛋白质磷酸化是调节离子型谷氨酸受体(IGluRs)的重要机制。早期的研究已经证实，主要的iGluR亚型，包括α-amino-3-hydroxy-5-methylisoxazole-4-propionic酸(AMPA)受体和N-甲基-D-天冬氨酸(NMDA)受体，都受到磷酸化的影响。多个丝氨酸、苏氨酸和酪氨酸残基主要位于AMPA受体和NMDA受体亚单位的C末端区域，已被确定为敏感的磷酸化位点。这些不同的位点经历结构性磷酸化或活性依赖的磷酸化，这些磷酸化是通过改变细胞和突触的输入作为可逆事件来诱导的。越来越多的突触丰富的蛋白激酶被发现使iGluR磷酸化。常见的蛋白激酶包括蛋白激酶A、蛋白激酶C、钙/钙调素依赖的蛋白激酶II、Src/Fyn非受体酪氨酸激酶和细胞周期蛋白依赖的激酶-5。调节的磷酸化在调节受体的生化、生物物理和功能特性方面发挥着广泛的作用。在未来，确定磷酸化如何调节iGluR活性的确切机制，并找到iGluR磷酸化与各种脑部疾病的发病机制之间的联系，包括精神和神经退行性疾病、慢性疼痛、中风、阿尔茨海默病和物质成瘾，将是热门话题，并可能通过针对明确的磷酸化过程来帮助开发新的药物疗法，以抑制iGluR相关疾病。
Protein phosphorylation is an important mechanism for regulating ionotropic glutamate receptors (iGluRs). Early studies have established that major iGluR subtypes, including α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and N-methyl-D-aspartate (NMDA) receptors, are subject to phosphorylation. Multiple serine, threonine, and tyrosine residues predominantly within the C-terminal regions of AMPA receptor and NMDA receptor subunits have been identified as sensitive phosphorylation sites. These distinct sites undergo either constitutive phosphorylation or activity-dependent phosphorylation induced by changing cellular and synaptic inputs as reversible events. An increasing number of synapse-enriched protein kinases have been found to phosphorylate iGluR. The common kinases include protein kinase A, protein kinase C, Ca2+/calmodulin-dependent protein kinase II, Src/Fyn non-receptor tyrosine kinases, and cyclin dependent kinase-5. Regulated phosphorylation plays a well-documented role in modulating the biochemical, biophysical, and functional properties of the receptor. In the future, identifying the precise mechanisms how phosphorylation regulates iGluR activities and finding the link between iGluR phosphorylation and the pathogenesis of various brain diseases, including psychiatric and neurodegenerative diseases, chronic pain, stroke, Alzheimer’s disease and substance addiction, will be hot topics and could contribute to the development of novel pharmacotherapies, by targeting the defined phosphorylation process, for suppressing iGluR-related disorders.
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