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研究揭示海马AMPA受体装配及变构抑制机制
2021-05-16 15:58

近日,美国俄勒冈健康与科学大学Eric Gouaux团队揭示海马AMPA受体装配及变构抑制机制。相关论文于2021年5月12日在线发表在《自然》杂志上。

研究人员使用免疫亲和纯化获得了小鼠海马的钙不可渗透AMPA受体复合物,并使用单分子荧光和低温电子显微镜实验性阐明了三种主要的AMPA受体-辅助亚基复合物。GluA1-GluA2、GluA1-GluA2-GluA3和GluA2-GluA3受体是主要的受体,辅助亚基TARP-γ8和CNIH2-SynDIG4分别非随机地位于B'/ D'和A'/ C'位置。研究人员进一步证明了受体-TARP-γ8的化学计量如何解释了临床相关脑区域特异性变构抑制剂的抑制作用和最大抑制作用。

据了解,AMPA选择性谷氨酸受体介导海马神经回路之间的信号转导。AMPA受体的运输、定位、动力学和药理作用通过一组辅助蛋白亚基进行调节,这些辅助蛋白亚基是与受体结合的完整膜蛋白,可产生真正的受体信号复合物。到目前为止,对利用工程蛋白构建的重组AMPA受体-辅助亚基复合物的广泛研究还不能如实地阐明海马AMPA受体复合物的分子结构。

附:英文原文

Title: Hippocampal AMPA receptor assemblies and mechanism of allosteric inhibition

Author: Jie Yu, Prashant Rao, Sarah Clark, Jaba Mitra, Taekjip Ha, Eric Gouaux

Issue&Volume: 2021-05-12

Abstract: 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.

DOI: 10.1038/s41586-021-03540-0

Source: https://www.nature.com/articles/s41586-021-03540-0

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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