2. Academic Validation
  3. Functional coupling of TRPM2 and extrasynaptic NMDARs exacerbates excitotoxicity in ischemic brain injury

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

  • Neuron. 2022 Jun 15;110(12):1944-1958.e8. doi: 10.1016/j.neuron.2022.03.021.
Pengyu Zong 1,  Jianlin Feng 1,  Zhichao Yue 1,  Yunfeng Li 2,  Gongxiong Wu 3,  Baonan Sun 1,  Yanlin He 1,  Barbara Miller 4,  Albert S Yu 1,  Zhongping Su 1,  Jia Xie 1,  Yasuo Mori 5,  Bing Hao 2,  Lixia Yue 6
Affiliations

Affiliations

  • 1 Department of Cell Biology, Calhoun Cardiology Center, University of Connecticut School of Medicine (UConn Health), Farmington, CT 06030, USA.
  • 2 Department of Molecular Biology and Biophysics, University of Connecticut School of Medicine (UConn Health), Farmington, CT 06030, USA.
  • 3 Department of Medicine, Brigham and Women's Hospital, Laboratory for Translational Research, Harvard Medical School, Cambridge, MA 02139, USA.
  • 4 Departments of Pediatrics and Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, P.O. Box 850, Hershey, PA 17033, USA.
  • 5 Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan; The World Premier International Research Initiative, Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto 615-8510, Japan.
  • 6 Department of Cell Biology, Calhoun Cardiology Center, University of Connecticut School of Medicine (UConn Health), Farmington, CT 06030, USA. Electronic address: lyue@uchc.edu.
PMID: 35421327 DOI: 10.1016/j.neuron.2022.03.021
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.

Keywords

Ca(2+) signaling; NMDA receptors; NMDARs; TRPM2; excitotoxicity; ischemic stroke; neuronal death; therapeutic peptide.

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