Nonselective cation permeation in an AMPA-type glutamate receptor.
Nonselective cation permeation in an AMPA-type glutamate receptor.
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DOI：
10.1073/pnas.2012843118
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发表时间：
2021-02-23
影响因子：
11.1
通讯作者：
Sun H
中科院分区：
文献类型：
--
作者：
Biedermann J;Braunbeck S;Plested AJR;Sun H
AMPA型谷氨酸受体(AMPAR)是兴奋性从一个脑细胞传递到另一个脑细胞的最后一步。该受体包含一个完整的离子通道，当被神经递质打开时，该通道允许钠和其他阳离子穿过细胞膜。我们使用计算分子动力学方法在原子水平上研究了钠、钾和铯的渗透，并在数十微秒的模拟过程中获得了与湿实验中类似的离子传输速率。我们确定在阳离子之间的区域选择是这类通道中最简单的。与选择单一离子物种的离子通道不同，钠和钾保持部分水合，并且在通道中只有一个主要结合部位。中枢神经系统的快速兴奋性突触传递依赖于AMPA型谷氨酸受体(AMPAR)。该受体结合了一个非选择性的阳离子通道，该通道由谷氨酸结合打开。尽管最近通过低温电子显微镜(Cryo-EM)获得了开放的孔结构，但调节AMPA受体阳离子通透性的分子机制尚不清楚。在这里，我们结合微秒分子动力学(MD)模拟推测的开放状态结构的GluA2和电生理学的克隆通道，以阐明离子渗透机制。Na+、K+和Cs+以生理速率渗透，与代表真正开放状态的结构一致。孔中Na+和K+的单一主要离子结合位置代表了任何已知结构的四聚阳离子通道中最简单的选择性过滤器(SF)结构。最小的SF只由Q586和Q587组成，其他残基在细胞质一侧形成一个锥形的充满水的空腔，缺乏与离子的主要相互作用。我们观察到ClGluA2很容易进入上孔，解释了−编辑(Q586R)形式的阴离子渗透。SF的允许结构允许不同的碱金属在不同的溶剂化状态下，允许快速的、非选择性的阳离子渗透和水的铜渗透。模拟表明Cs+在过滤器中使用两个相同填充的离子结合位点，我们用GluA2的电生理学证实了Cs+比Na+稍微更有意义，与优先驱动选择性的系列结合位点一致。
AMPA-type glutamate receptors (AMPARs) make the final step in a relay of excitability from one brain cell to another. The receptor contains an integral ion channel, which, when opened by neurotransmitter, permits sodium and other cations to cross the cell membrane. We investigated permeation of sodium, potassium, and cesium at the atomistic level using a computational molecular dynamics approach and obtained ion transit rates similar to those in wet experiments over tens of microseconds of simulations. We determined that the region selecting between cations is the simplest of any channel of this type. Distinct from ion channels that select single ion species, sodium and potassium remain partly hydrated and have only one major binding site in the channel. Fast excitatory synaptic transmission in the central nervous system relies on the AMPA-type glutamate receptor (AMPAR). This receptor incorporates a nonselective cation channel, which is opened by the binding of glutamate. Although the open pore structure has recently became available from cryo-electron microscopy (Cryo-EM), the molecular mechanisms governing cation permeability in AMPA receptors are not understood. Here, we combined microsecond molecular dynamic (MD) simulations on a putative open-state structure of GluA2 with electrophysiology on cloned channels to elucidate ion permeation mechanisms. Na+, K+, and Cs+ permeated at physiological rates, consistent with a structure that represents a true open state. A single major ion binding site for Na+ and K+ in the pore represents the simplest selectivity filter (SF) structure for any tetrameric cation channel of known structure. The minimal SF comprised only Q586 and Q587, and other residues on the cytoplasmic side formed a water-filled cavity with a cone shape that lacked major interactions with ions. We observed that Cl− readily enters the upper pore, explaining anion permeation in the RNA-edited (Q586R) form of GluA2. A permissive architecture of the SF accommodated different alkali metals in distinct solvation states to allow rapid, nonselective cation permeation and copermeation by water. Simulations suggested Cs+ uses two equally populated ion binding sites in the filter, and we confirmed with electrophysiology of GluA2 that Cs+ is slightly more permeant than Na+, consistent with serial binding sites preferentially driving selectivity.
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DOI：
10.1085/jgp.27.1.37
发表时间：
1943-09-20
期刊：
The Journal of general physiology
影响因子：
--
作者：
Goldman DE
通讯作者：
Goldman DE
影响因子：
56.9
作者：
Doyle, DA;Cabral, JM;MacKinnon, R
通讯作者：
MacKinnon, R
影响因子：
16.8
作者：
通讯作者：
--
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
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