美国俄勒冈健康与科学大学Eric Gouaux课题组的研究发现原生Ca²⁺渗透性AMPA受体的门控和新细胞聚集。2025年6月23日出版的《自然》发表了这项成果。

为了阐明CP-AMPARs的亚基组成、生理结构和门控机制，该团队首次展示了这些从大鼠小脑中纯化的免疫亲和受体的可视化，并利用冷冻电镜（cro-EM）解析了它们的结构。他们的结果表明，主要的组装由GluA1和GluA4亚基组成，其中GluA4亚基位于B和D位置，而辅助亚基，包括TARPs，位于B' /D'位置，CNIHs或TARPs位于A' /C'位置。

此外，该团队解析了Noelin 1- GluA1/A4复合物的结构，其中Noelin 1（noe1）特异性地结合在GluA4亚基的B和D位置。值得注意的是，Noe 1稳定了氨基末端结构域（ATD）层，而不影响受体的门控特性。Noe 1通过形成二聚体-AMPAR组件来促进AMPAR功能，这些组件可能参与细胞外网络，在突触环境中聚集受体并调节受体对突触输入的反应。

据介绍，AMPAR型嗜离子性谷氨酸受体（AMPARs）是快速兴奋性突触传递的组成部分，在突触可塑性、运动协调、学习和记忆中发挥重要作用。虽然对重组AMPARs和天然钙不透性(CI)-AMPARs及其辅助蛋白进行了广泛的结构研究，但天然钙透性(CP)-AMPARs的分子结构仍不明确。

附：英文原文

Title: Gating and noelin clustering of native Ca2+-permeable AMPA receptors

Author: Fang, Chengli, Spangler, Cathy J., Park, Jumi, Sheldon, Natalie, Trussell, Laurence O., Gouaux, Eric

Issue&Volume: 2025-06-23

Abstract: AMPA-type ionotropic glutamate receptors (AMPARs) are integral to fast excitatory synaptic transmission and play vital roles in synaptic plasticity, motor coordination, learning, and memory1. While extensive structural studies have been conducted on recombinant AMPARs and native calcium impermeable (CI)-AMPARs alongside their auxiliary proteins2-5, the molecular architecture of native calcium permeable (CP)-AMPARs has remained undefined. To elucidate the subunit composition, physiological architecture, and gating mechanisms of CP-AMPARs, here we present the first visualization of these receptors, immunoaffinity purified from rat cerebella, and resolve their structures using cryo-electron microscopy (cryo-EM). Our results indicate that the predominant assembly consists of GluA1 and GluA4 subunits, with the GluA4 subunit occupying the B and D positions, while auxiliary subunits, including TARPs, are located at the B′/D′ positions and CNIHs or TARPs at the A′/C′ positions. Furthermore, we resolved the structure of the Noelin 1-GluA1/A4 complex, wherein Noelin 1 (Noe 1) specifically binds to the GluA4 subunit at the B and D positions. Notably, Noe 1 stabilizes the amino-terminal domain (ATD) layer without affecting receptor gating properties. Noe 1 contributes to AMPAR function by forming dimeric-AMPAR assemblies that likely engage in extracellular networks, clustering receptors within synaptic environments and modulating receptor responsiveness to synaptic inputs.

DOI: 10.1038/s41586-025-09289-0

Source: https://www.nature.com/articles/s41586-025-09289-0