Atomistic mechanism for the activation and desensitization of an AMPA-subtype glutamate receptor.
Atomistic mechanism for the activation and desensitization of an AMPA-subtype glutamate receptor.
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DOI：
10.1038/ncomms1362
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发表时间：
2011-06-14
影响因子：
16.6
通讯作者：
Zhou HX
中科院分区：
文献类型：
--
作者：
Dong H;Zhou HX
离子型谷氨酸受体（iGluRs）介导中枢神经系统中的快速兴奋性突触传递。在激动剂结合时，iGluR打开以允许阳离子流动，随后进入脱敏状态。目前尚不清楚激动剂如何结合配体结合结构域被传递到跨膜结构域的通道激活和脱敏。在这里，我们报告的AMPA亚型iGluR在明确的水和膜的分子动力学模拟。在激活和脱敏过程的模拟中观察到通道的打开和关闭。LBD-TMD连接体沿着受体中心轴和在侧平面中的运动协同地促进通道的打开和关闭。这里的模拟所建议的通道激活和脱敏的详细机制与现有的数据是一致的，可以作为新的实验和药理学试剂的设计的指导。
Ionotropic glutamate receptors (iGluRs) mediate fast excitatory synaptic transmission in the central nervous system. Upon agonist binding, an iGluR opens to allow the flow of cations and subsequently enters into a desensitized state. It remains unclear how agonist binding to the ligand-binding domain is transmitted to the transmembrane domain for channel activation and desensitization. Here we report molecular dynamics simulations of an AMPA-subtype iGluR in explicit water and membrane. Channel opening and closing were observed in simulations of the activation and desensitization processes, respectively. The motions of the LBD-TMD linkers along the central axis of the receptor and in the lateral plane contributed cooperatively to channel opening and closing. The detailed mechanism of channel activation and desensitization suggested by the simulations here is consistent with existing data and may serve as a guide for new experiments and for the design of pharmacological agents.