SNARE proteins are essential in the potentiation of NMDA receptors by group II metabotropic glutamate receptors
SNARE proteins are essential in the potentiation of NMDA receptors by group II metabotropic glutamate receptors
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DOI：
10.1113/jphysiol.2013.255075
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发表时间：
2013-08-15
影响因子：
5.5
通讯作者：
Yan, Zhen
中科院分区：
文献类型：
--
作者：
Cheng, Jia;Liu, Wenhua;Yan, Zhen
II 类代谢型谷氨酸受体（II 类 mGluR）已成为治疗精神分裂症等精神疾病的新药物靶点。为了了解 II 类 mGluR 抗精神病作用的潜在机制，我们检查了它们对 NMDA 受体 (NMDAR) 的影响，因为 NMDAR 功能减退与精神分裂症有关。 II 组 mGluR 的激活引起皮质锥体神经元中 NMDAR 电流的显着增强，这与 NMDAR 表面表达和突触定位的增加有关。我们进一步研究了 II 组 mGluR 的这些作用是否是通过 SNARE 蛋白（参与囊泡融合的蛋白家族）调节 NMDAR 胞吐作用。我们发现，当肉毒杆菌毒素被递送到记录的神经元中以破坏 SNARE 复合体时，APDC（II 组 mGluRs 的选择性激动剂）对 NMDAR 电流的增强作用被消除。抑制两个关键 SNARE 蛋白 SNAP-25 和 Syntaxin 4 的功能，也消除了 APDC 对 NMDAR 电流的影响。此外，APDC的应用增加了Rab4的活性，Rab4是一种小型Rab GTP酶，介导从早期内体到质膜的快速循环，并增强了突触融合蛋白4和Rab4之间的相互作用。 Rab4 的敲低或显性失活 Rab4 的表达减弱了 APDC 对 NMDAR 电流的影响。总而言之，这些结果确定了参与 II 组 mGluR 诱导的 NMDAR 胞吐作用和功能增强的关键分子。
The group II metabotropic glutamate receptors (group II mGluRs) have emerged as the new drug targets for the treatment of mental disorders like schizophrenia. To understand the potential mechanisms underlying the antipsychotic effects of group II mGluRs, we examined their impact on NMDA receptors (NMDARs), since NMDAR hypofunction has been implicated in schizophrenia. The activation of group II mGluRs caused a significant enhancement of NMDAR currents in cortical pyramidal neurons, which was associated with increased NMDAR surface expression and synaptic localization. We further examined whether these effects of group II mGluRs are through the regulation of NMDAR exocytosis via SNARE proteins, a family of proteins involved in vesicle fusion. We found that the enhancing effect of APDC, a selective agonist of group II mGluRs, on NMDAR currents was abolished when botulinum toxin was delivered into the recorded neurons to disrupt the SNARE complex. Inhibiting the function of two key SNARE proteins, SNAP-25 and syntaxin 4, also eliminated the effect of APDC on NMDAR currents. Moreover, the application of APDC increased the activity of Rab4, a small Rab GTPase mediating fast recycling from early endosomes to the plasma membrane, and enhanced the interaction between syntaxin 4 and Rab4. Knockdown of Rab4 or expression of dominant-negative Rab4 attenuated the effect of APDC on NMDAR currents. Taken together, these results have identified key molecules involved in the group II mGluR-induced potentiation of NMDAR exocytosis and function.