NMDA Receptors Require Multiple Pre-opening Gating Steps for Efficient Synaptic Activity.
NMDA Receptors Require Multiple Pre-opening Gating Steps for Efficient Synaptic Activity.
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DOI：
10.1016/j.neuron.2020.11.009
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发表时间：
2021-02-03
期刊：
影响因子：
16.2
通讯作者：
Wollmuth LP
中科院分区：
文献类型：
--
作者：
Amin JB;Gochman A;He M;Certain N;Wollmuth LP
NMDA受体（NMDAR）是谷氨酸门控离子通道，在神经系统中介导快速兴奋性突触传递。将谷氨酸应用于含有单个NMDAR的外向补丁，我们发现激动剂结合的受体通过两种构象过渡到开放状态，一种是有助于快速突触事件的“不受约束的预激活”状态，另一种是不受约束的预激活状态。为了确定谷氨酸如何驱动这些构象，我们将配体结合结构域与GluN 1和GluN 2A的特定跨膜片段分离。成孔M3段的位移定义了快速打开的能量。然而，为了进入不受约束的构象并有助于快速信号传导，GluN 2前M1螺旋必须在M3片段移动之前被置换。GluN 1和GluN 2A的S2-M4的灵活性促进了这种前M1置换。因此，外部结构-前M1和S2-M4 -协同工作，以消除限制，并为通道的快速开放做好准备，促进快速突触传递。NMDA受体是调节高级脑功能的神经递质门控离子通道。使用一种独特的技术来测定神经递质诱导的离子通道开放和可用的高分辨率结构，Amin等人提供了一个框架来理解调节突触处NMDA受体激活活性的结构基础。
NMDA receptors (NMDAR) are glutamate-gated ion channels that mediate fast excitatory synaptic transmission in the nervous system. Applying glutamate to outside-out patches containing a single NMDAR, we find that agonist-bound receptors transition to the open state via two conformations, an ‘unconstrained pre-active’ state that contributes to fast synaptic events, and a ‘constrained pre-active’ state that does not. To define how glutamate drives these conformations, we decoupled the ligand-binding domains from specific transmembrane segments for GluN1 and GluN2A. Displacements of the pore-forming M3 segments define the energy of fast opening. However, to enter the unconstrained conformation and contribute to fast signaling, the GluN2 pre-M1 helix must be displaced before the M3 segments move. This pre-M1 displacement is facilitated by the flexibility of the S2-M4 of GluN1 and GluN2A. Thus, outer structures - pre-M1 and S2-M4 - work in concert to remove constraints and prime the channel for rapid opening, facilitating fast synaptic transmission. NMDA receptors are neurotransmitter-gated ion channels that regulate higher brain function. Using a unique technique to assay neurotransmitter-induced opening of the ion channel and available high-resolution structures, Amin et al. provides a framework to understand the structural underpinnings that regulate the activity of NMDA receptor activation at synapses.
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DOI：
10.1007/978-1-4939-7321-7_1
发表时间：
2017
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Hansen KB;Yi F;Perszyk RE;Menniti FS;Traynelis SF
通讯作者：
Traynelis SF
影响因子：
16.6
作者：
通讯作者：
--
影响因子：
14.8
作者：
Dolino DM;Chatterjee S;MacLean DM;Flatebo C;Bishop LDC;Shaikh SA;Landes CF;Jayaraman V
通讯作者：
Jayaraman V
影响因子：
5.3
作者：
Chang, Huai-Ren;Kuo, Chung-Chin
通讯作者：
Kuo, Chung-Chin
影响因子：
64.5
作者：
Chen S;Zhao Y;Wang Y;Shekhar M;Tajkhorshid E;Gouaux E
通讯作者：
Gouaux E