Glutamate gating of AMPA-subtype iGluRs at physiological temperatures

• 成果类型: Article
• 署名作者: Mondal, Anish Kumar; Carrillo, Elisa; Jayaraman, Vasanthi; Twomey, Edward C.
• 署名单位: Johns Hopkins University; Johns Hopkins University; University of Texas System; University of Texas Health Science Center Houston; University of Texas System; UTMD Anderson Cancer Center; University of Texas Health Science Center Houston; Johns Hopkins University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2172
• DOI: 10.1038/s41586-025-08770-0
• 发表日期: 2025-05-15
• 关键词: receptor-channel; lurcher mutation; structural bases; desensitization; conductance; inhibition; mechanisms; dependence; responses; kinetics

摘要

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 alpha-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.