英国MRC分子生物学实验室Ingo H. Greger最新研究发现结构迁移调节GluA1 AMPA谷氨酸受体信号传导。2023年9月13日出版的《自然》杂志发表了这项成果。

研究人员解析GluA1同型四聚体的冷冻电微镜结构，该结构完全被TARPγ3辅助亚基（GluA1 / γ3）包被。静息状态和开放状态 GluA1/γ3 的门控核心与含 GluA2 的受体非常相似。

然而，序列多样的N端结构域（NTD）产生了高度可变的组装，使配体结合结构域层中的结构域交换和亚基重新排列成为可能，这些结构域在脱敏状态下更明显。这些转变是GluA1发挥独特动力学特性的基础。NTD变动增加的GluA2突变体（F231A）表现出这种行为，并表现出减弱的突触反应，这证明AMPAR NTD在突触上的锚定功能。总之，该研究工作揭示了亚基多样性NTDs如何调控AMPAR亚型中的亚基排列、门控特性以及如何影响最终突触信号的传导效率。

据了解，AMPA 谷氨酸受体 （AMPAR） 是大脑中兴奋性神经元传递的主要介质，若含有 GluA2 亚基则导致Ca²⁺渗透缺失，如果缺乏 GluA2 那 Ca²⁺ 可渗透。尽管它们主要在整个中间神经元和神经胶质细胞中表达，并发挥长期增强作用以及参与一系列神经病理学，但目前缺乏GluA2受体的结构信息。

附：英文原文

Title: Structural mobility tunes signalling of the GluA1 AMPA glutamate receptor

Author: Zhang, Danyang, Ivica, Josip, Krieger, James M., Ho, Hinze, Yamashita, Keitaro, Stockwell, Imogen, Baradaran, Rozbeh, Cais, Ondrej, Greger, Ingo H.

Issue&Volume: 2023-09-13

Abstract: AMPA glutamate receptors (AMPARs), the primary mediators of excitatory neurotransmission in the brain, are either GluA2 subunit-containing and thus Ca2+-impermeable, or GluA2-lacking and Ca2+-permeable1. Despite their prominent expression throughout interneurons and glia, their role in long-term potentiation and their involvement in a range of neuropathologies2, structural information for GluA2-lacking receptors is currently absent. Here we determine and characterize cryo-electron microscopy structures of the GluA1 homotetramer, fully occupied with TARPγ3 auxiliary subunits (GluA1/γ3). The gating core of both resting and open-state GluA1/γ3 closely resembles GluA2-containing receptors. However, the sequence-diverse N-terminal domains (NTDs) give rise to a highly mobile assembly, enabling domain swapping and subunit re-alignments in the ligand-binding domain tier that are pronounced in desensitized states. These transitions underlie the unique kinetic properties of GluA1. A GluA2 mutant (F231A) increasing NTD dynamics phenocopies this behaviour, and exhibits reduced synaptic responses, reflecting the anchoring function of the AMPAR NTD at the synapse. Together, this work underscores how the subunit-diverse NTDs determine subunit arrangement, gating properties and ultimately synaptic signalling efficiency among AMPAR subtypes. Calcium-permeable GluA1 AMPA glutamate receptors are structurally and functionally distinct from the prototypical GluA2-containing AMPA receptors, impacting their role in signal transmission, synaptic plasticity and learning.

DOI: 10.1038/s41586-023-06528-0

Source: https://www.nature.com/articles/s41586-023-06528-0