A single GluN2 subunit residue controls NMDA receptor channel properties via intersubunit interaction.
A single GluN2 subunit residue controls NMDA receptor channel properties via intersubunit interaction.
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DOI：
10.1038/nn.3025
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发表时间：
2012-01-15
影响因子：
25
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中科院分区：
文献类型：
--
作者：
NMDAR是一种谷氨酸门控离子通道，存在于大多数兴奋性哺乳动物突触中。GluN2的四个亚基(GluN2A-D)构成了四种不同的NMDAR亚型，它们发挥着不同的生理和病理作用。NMDAR功能的基本频道属性因子类型而异。我们通过创建和检查包含突变的GluN2亚基的NMDAR来研究导致通道特性变化的氨基酸残基。出乎意料的是，我们发现NMDAR亚型的三个关键特性，即镁离子阻断、对钙的选择性通透性和单通道电导，都主要受M3跨膜区单个GluN2位点的残基控制。分子模拟指导的突变循环分析表明，GluN2-GluN1亚基相互作用介导了该位点的影响。我们的结论是，单个GluN2亚基残基与GluN1亚基的造孔环耦合，从而产生自然发生的NMDAR属性变异，这对突触的可塑性和学习至关重要。
NMDA receptors (NMDARs) are glutamate-gated ion channels present at most excitatory mammalian synapses. The four GluN2 subunits (GluN2A–D) contribute to four diheteromeric NMDAR subtypes that play divergent physiological and pathological roles. Channel properties fundamental to NMDAR function vary among subtypes. We investigated the amino acid residues responsible for variations in channel properties by creating and examining NMDARs containing mutant GluN2 subunits. Unexpectedly, we found that the NMDAR subtype specificity of three crucial channel properties, Mg2+ block, selective permeability to Ca2+, and single-channel conductance, all are controlled primarily by the residue at a single GluN2 site in the M3 transmembrane region. Mutant cycle analysis guided by molecular modeling revealed that a GluN2-GluN1 subunit interaction mediates the site’s effects. We conclude that a single GluN2 subunit residue couples with the pore-forming loop of the GluN1 subunit to create naturally-occurring variations in NMDAR properties that are critical to synaptic plasticity and learning.
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影响因子：
56.9
作者：
Doyle, DA;Cabral, JM;MacKinnon, R
通讯作者：
MacKinnon, R
影响因子：
64.8
作者：
Gielen, Marc;Retchless, Beth Siegler;Mony, Laetitia;Johnson, Jon W.;Paoletti, Pierre
通讯作者：
Paoletti, Pierre
影响因子：
5.3
作者：
Jones, KS;VanDongen, HMA;VanDongen, AMJ
通讯作者：
VanDongen, AMJ
影响因子：
5.3
作者：
Clarke, Richard J.;Johnson, Jon W.
通讯作者：
Johnson, Jon W.
影响因子：
56.9
作者：
HIDALGO, P;MACKINNON, R
通讯作者：
MACKINNON, R