AMPA受体
变构调节
受体
海马结构
蛋白质亚单位
生物物理学
谷氨酸受体
细胞生物学
变构调节剂
化学
白细胞介素-13受体
生物
生物化学
神经科学
基因
胰岛素样生长因子1受体
生长因子
作者
Jie Yu,Prashant Rao,Sarah Clark,Jaba Mitra,Taekjip Ha,Eric Gouaux
出处
期刊:Nature
[Springer Nature]
日期:2021-05-12
卷期号:594 (7863): 448-453
被引量:51
标识
DOI:10.1038/s41586-021-03540-0
摘要
AMPA-selective glutamate receptors mediate the transduction of signals between the neuronal circuits of the hippocampus1. The trafficking, localization, kinetics and pharmacology of AMPA receptors are tuned by an ensemble of auxiliary protein subunits, which are integral membrane proteins that associate with the receptor to yield bona fide receptor signalling complexes2. Thus far, extensive studies of recombinant AMPA receptor-auxiliary subunit complexes using engineered protein constructs have not been able to faithfully elucidate the molecular architecture of hippocampal AMPA receptor complexes. Here we obtain mouse hippocampal, calcium-impermeable AMPA receptor complexes using immunoaffinity purification and use single-molecule fluorescence and cryo-electron microscopy experiments to elucidate three major AMPA receptor-auxiliary subunit complexes. The GluA1-GluA2, GluA1-GluA2-GluA3 and GluA2-GluA3 receptors are the predominant assemblies, with the auxiliary subunits TARP-γ8 and CNIH2-SynDIG4 non-stochastically positioned at the B'/D' and A'/C' positions, respectively. We further demonstrate how the receptor-TARP-γ8 stoichiometry explains the mechanism of and submaximal inhibition by a clinically relevant, brain-region-specific allosteric inhibitor.
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