Kumar Mondal Anish, Carrillo Elisa, Jayaraman Vasanthi, Twomey Edward C
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Nature. 2025 May;641(8063):788-796. doi: 10.1038/s41586-025-08770-0. Epub 2025 Mar 26.
Ionotropic glutamate receptors (iGluRs) are tetrameric ligand-gated ion channels that mediate most excitatory neurotransmission. iGluRs are gated by glutamate, where on glutamate binding, they open their ion channels to enable cation influx into postsynaptic neurons, initiating signal transduction. 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.
离子型谷氨酸受体（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由谷氨酸激活，谷氨酸结合后，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中谷氨酸门控是如何发生的结构机制尚不清楚。在这里，我们使用α-氨基-3-羟基-5-甲基-4-异恶唑丙酸亚型iGluR（AMPAR）确定了谷氨酸门控机制。在生理温度下，谷氨酸对AMPAR的激活作用增强。通过在这些温度下为低温电子显微镜制备AMPAR，我们捕捉到了谷氨酸门控机制。谷氨酸激活引发离子通道开放，这涉及所有离子通道螺旋以一种在所有iGluRs中保守的模式从孔轴处铰链分开。当局部二聚体对解偶联并通过恢复通道铰链和重新折叠通道门使下方的离子通道关闭时，脱敏发生。我们的研究结果确定了谷氨酸如何门控iGluRs，为治疗设计提供了基础，并证明了生理温度如何改变iGluR功能。
