约翰霍普金斯大学医学院Edward C. Twomey团队近日取得一项新成果。经过不懈努力，他们揭示了生理温度下AMPA亚型iGluRs的谷氨酸门控。相关论文于2025年3月26日发表于国际顶尖学术期刊《自然》杂志上。

以α-氨基-3-羟基-5-甲基-4-异恶唑丙酸亚型iGluR （AMPAR）为主题，该团队确定了谷氨酸门控机制。谷氨酸对AMPAR的激活在生理温度下增强。通过在这些温度下为低温电子显微镜制备AMPAR，该研究团队捕获了谷氨酸门控机制。谷氨酸的激活启动了离子通道的开放，包括所有的离子通道螺旋在所有iGluRs中都是保守的基序中从孔轴上移开。脱敏发生在局部二聚体对解耦时，通过恢复通道铰链和重新折叠通道门，使下面的离子通道关闭。他们的发现定义了谷氨酸如何控制iGluRs，为治疗设计提供了基础，并展示了生理温度如何改变iGluRs的功能。

据悉，嗜离子性谷氨酸受体（iGluRs）是四聚体配体门控离子通道，介导大多数兴奋性神经传递。iGluRs由谷氨酸控制，在谷氨酸结合时，它们打开离子通道，使阳离子流入突触后神经元，启动信号转导。全长iGluRs中谷氨酸门控发生的结构机制尚不清楚。

附：英文原文

Title: Glutamate gating of AMPA-subtype iGluRs at physiological temperatures

Author: Kumar Mondal, Anish, Carrillo, Elisa, Jayaraman, Vasanthi, Twomey, Edward C.

Issue&Volume: 2025-03-26

Abstract: Ionotropic glutamate receptors (iGluRs) are tetrameric ligand-gated ion channels that mediate most excitatory neurotransmission1. iGluRs are gated by glutamate, where on glutamate binding, they open their ion channels to enable cation influx into postsynaptic neurons, initiating signal transduction1,2. The structural mechanics of how glutamate gating occurs in full-length iGluRs is not well understood. Here, using the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtype iGluR (AMPAR), we identify the glutamate-gating mechanism. AMPAR activation by glutamate is augmented at physiological temperatures. By preparing AMPARs for cryogenic-electron microscopy at these temperatures, we captured the glutamate-gating mechanism. Activation by glutamate initiates ion channel opening that involves all ion channel helices hinging away from the pore axis in a motif that is conserved across all iGluRs. Desensitization occurs when the local dimer pairs decouple and enables closure of the ion channel below through restoring the channel hinges and refolding the channel gate. Our findings define how glutamate gates iGluRs, provide foundations for therapeutic design and demonstrate how physiological temperatures can alter iGluR function.

DOI: 10.1038/s41586-025-08770-0

Source: https://www.nature.com/articles/s41586-025-08770-0