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CaMKII介导的谷氨酸受体磷酸化

毛利民, 金道忠, 薛冰, 储祥平, 王强^*

密苏里州立大学医学院基础医学系，密苏里州堪萨斯城 64108，美国

摘要

钙/钙调蛋白依赖的蛋白激酶II (Ca2+/calmodulin-dependent protein kinase II, CaMKII)在脑内兴奋性突触部位丰富表达。通过催化谷氨酸受体和众多突触蛋白磷酸化，CaMKII调节磷酸化蛋白在基础或细胞兴奋时的转运、分布和功能。谷氨酸NMDA受体是CaMKII的直接底物，有证据表明CaMKII直接与NMDA受体胞内C末端相互结合，催化一特定丝氨酸(S1303)的磷酸化。CaMKII也加强谷氨酸AMPA受体的磷酸化，通过磷酸化AMPA受体C末端特定的丝氨酸(S831)，CaMKII增强AMPA受体的功能。此外，CaMKII可与代谢型谷氨酸受体mGluR1亚型的胞内C末端结合，促进一特定苏氨酸(T871)的磷酸化，从而促进受体兴奋后脱敏。CaMKII在正常状态下与mGluR5受体结合以储存于突触内，刺激mGluR5受体时，CaMKII与mGluR5受体分离，转运至NMDA受体，以介导mGluR5信号对NMDA受体的增强作用。总之，CaMKII与谷氨酸受体相互作用，改变受体磷酸化水平，参与受体的数量和功能以及突触传导活动的调节。

关键词： NMDA; GluN2B; AMPA; GluA1; 代谢型谷氨酸受体; 蛋白激酶; 钙调蛋白; 突触可塑性

Phosphorylation and regulation of glutamate receptors by CaMKII

MAO Li-Min, JIN Dao-Zhong, XUE Bing, CHU Xiang-Ping, WANG John Q^*

Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA

Abstract

Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) is the most abundant kinase within excitatory synapses in the mammalian brain. It interacts with and phosphorylates a large number of synaptic proteins, including major ionotropic glutamate receptors (iGluRs) and group I metabotropic glutamate receptors (mGluRs), to constitutively and/or activity-dependently regulate trafficking, subsynaptic localization, and function of the receptors. Among iGluRs, the N-methyl-D-aspartate receptor (NMDAR) is a direct target of CaMKII. By directly binding to an intracellular C-terminal (CT) region of NMDAR GluN2B subunits, CaMKII phosphorylates a serine residue (S1303) in the GluN2B CT. CaMKII also phosphorylates a serine site (S831) in the CT of α-amino-3-hydroxy-5- methylisoxazole-4-propionic acid receptors. This phosphorylation enhances channel conductance and is critical for synaptic plasticity. In addition to iGluRs, CaMKII binds to the proximal CT region of mGluR1a, which enables the kinase to phosphorylate threonine 871. Agonist stimulation of mGluR1a triggers a CaMKII-mediated negative feedback to facilitate endocytosis and desensitization of the receptor. CaMKII also binds to the mGluR5 CT. This binding seems to anchor and accumulate inactive CaMKII at synaptic sites. Active CaMKII dissociates from mGluR5 and may then bind to adjacent GluN2B to mediate the mGluR5-NMDAR coupling. Together, glutamate receptors serve as direct substrates of CaMKII. By phosphorylating these receptors, CaMKII plays a central role in controlling the number and activity of the modified receptors and determining the strength of excitatory synaptic transmission.

Key words: NMDA; GluN2B; AMPA; GluA1; mGluR; PKC; calmodulin; synaptic plasticity

收稿日期：2013-12-04　　录用日期：2014-03-04

通讯作者：王强　　E-mail: wangjq@umkc.edu

引用本文：

毛利民, 金道忠, 薛冰, 储祥平, 王强. CaMKII介导的谷氨酸受体磷酸化[J]. 生理学报 2014; 66 (3): 365-372.

MAO Li-Min, JIN Dao-Zhong, XUE Bing, CHU Xiang-Ping, WANG John Q. Phosphorylation and regulation of glutamate receptors by CaMKII. Acta Physiol Sin 2014; 66 (3): 365-372 (in Chinese with English abstract).