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异八聚体AMPA谷氨酸受体的门控和调节机制获解析
2021-06-06 14:56

英国剑桥大学Ingo H. Greger研究团队解析异八聚体AMPA谷氨酸受体的门控和调节机制。2021年6月2日,国际知名学术期刊《自然》在线发表了这一成果。

研究人员解析了异聚体GluA1-GluA2受体的冷冻电镜结构,该受体与TARP-γ8和CNIH2组装在一起,并处于静止状态和活跃状态。两个TARP-γ8和两个CNIH2亚基插入受体配体结合域下方的不同位点,并且位点特异性脂质塑造了每个相互作用并影响AMPA受体的门控调节。受体的激活导致GluA1和GluA2沿离子传导路径不对称,通道的向外扩张触发两个辅助亚基对的反向旋转,并促进活性状态构象。

此外,TARP-γ8和CNIH2在激活后都转向孔出口,从而扩展了它们对细胞质受体元件的影响。CNIH2通过其独特的延伸M2螺旋实现了这一目标,并将这种内质网输出因子转化为强大的AMPA受体调节剂,从而能够为海马锥体神经元提供其整合突触特性。

据介绍,AMPA受体介导了大脑中的大部分兴奋性传递,并使作为学习基础的突触可塑性成为可能。受体辅助亚基建立了多种AMPA受体信号复合物,它们以各种组合与AMPA受体相关联,进而调节运输、门控和突触强度。然而,对它们的作用机制知之甚少。

附:英文原文

Title: Gating and modulation of a hetero-octameric AMPA glutamate receptor

Author: Danyang Zhang, Jake F. Watson, Peter M. Matthews, Ondrej Cais, Ingo H. Greger

Issue&Volume: 2021-06-02

Abstract: AMPA receptors (AMPARs) mediate the majority of excitatory transmission in the brain and enable the synaptic plasticity that underlies learning1. A diverse array of AMPAR signalling complexes are established by receptor auxiliary subunits, which associate with the AMPAR in various combinations to modulate trafficking, gating and synaptic strength2. However, their mechanisms of action are poorly understood. Here we determine cryo-electron microscopy structures of the heteromeric GluA1–GluA2 receptor assembled with both TARP-γ8 and CNIH2, the predominant AMPAR complex in the forebrain, in both resting and active states. Two TARP-γ8 and two CNIH2 subunits insert at distinct sites beneath the ligand-binding domains of the receptor, with site-specific lipids shaping each interaction and affecting the gating regulation of the AMPARs. Activation of the receptor leads to asymmetry between GluA1 and GluA2 along the ion conduction path and an outward expansion of the channel triggers counter-rotations of both auxiliary subunit pairs, promoting the active-state conformation. In addition, both TARP-γ8 and CNIH2 pivot towards the pore exit upon activation, extending their reach for cytoplasmic receptor elements. CNIH2 achieves this through its uniquely extended M2 helix, which has transformed this endoplasmic reticulum-export factor into a powerful AMPAR modulator that is capable of providing hippocampal pyramidal neurons with their integrative synaptic properties.

DOI: 10.1038/s41586-021-03613-0

Source: https://www.nature.com/articles/s41586-021-03613-0

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
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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