Functional coupling of TRPM2 and extrasynaptic NMDARs exacerbates excitotoxicity in ischemic brain injury

Pengyu Zong, Jianlin Feng, Zhichao Yue, Yunfeng Li, Gongxiong Wu, Baonan Sun, Yanlin He, Barbara Miller, Albert S. Yu, Zhongping Su, Jia Xie, Yasuo Mori, Bing Hao, Lixia Yue

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Excitotoxicity induced by NMDA receptor (NMDAR) activation is a major cause of neuronal death in ischemic stroke. However, past efforts of directly targeting NMDARs have unfortunately failed in clinical trials. Here, we reveal an unexpected mechanism underlying NMDAR-mediated neurotoxicity, which leads to the identification of a novel target and development of an effective therapeutic peptide for ischemic stroke. We show that NMDAR-induced excitotoxicity is enhanced by physical and functional coupling of NMDAR to an ion channel TRPM2 upon ischemic insults. TRPM2-NMDAR association promotes the surface expression of extrasynaptic NMDARs, leading to enhanced NMDAR activity and increased neuronal death. We identified a specific NMDAR-interacting motif on TRPM2 and designed a membrane-permeable peptide to uncouple the TRPM2-NMDAR interaction. This disrupting peptide protects neurons against ischemic injury in vitro and protects mice against ischemic stroke in vivo. These findings provide an unconventional strategy to mitigate excitotoxic neuronal death without directly targeting NMDARs.

Original languageEnglish (US)
Pages (from-to)1944-1958.e8
JournalNeuron
Volume110
Issue number12
DOIs
StatePublished - Jun 15 2022

All Science Journal Classification (ASJC) codes

  • General Neuroscience

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