TRPM2 enhances ischemic excitotoxicity by associating with PKCγ

Pengyu Zong, Jianlin Feng, Nicholas Legere, Yunfeng Li, Zhichao Yue, Cindy X. Li, Yasuo Mori, Barbara Miller, Bing Hao, Lixia Yue

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

N-methyl-D-aspartate receptor (NMDAR)-mediated glutamate excitotoxicity significantly contributes to ischemic neuronal death and post-recanalization infarction expansion. Despite tremendous efforts, targeting NMDARs has proven unsuccessful in clinical trials for mitigating brain injury. Here, we show the discovery of an interaction motif for transient receptor potential melastatin 2 (TRPM2) and protein kinase Cγ (PKCγ) association and demonstrate that TRPM2-PKCγ uncoupling is an effective therapeutic strategy for attenuating NMDAR-mediated excitotoxicity in ischemic stroke. We demonstrate that the TRPM2-PKCγ interaction allows TRPM2-mediated Ca2+ influx to promote PKCγ activation, which subsequently enhances TRPM2-induced potentiation of extrasynaptic NMDAR (esNMDAR) activity. By identifying the PKCγ binding motif on TRPM2 (M2PBM), which directly associates with the C2 domain of PKCγ, an interfering peptide (TAT-M2PBM) is developed to disrupt TRPM2-PKCγ interaction without compromising PKCγ function. M2PBM deletion or TRPM2-PKCγ dissociation abolishes both TRPM2-PKCγ and TRPM2-esNMDAR couplings, resulting in reduced excitotoxic neuronal death and attenuated ischemic brain injury.

Original languageEnglish (US)
Article number113722
JournalCell Reports
Volume43
Issue number2
DOIs
StatePublished - Feb 27 2024

All Science Journal Classification (ASJC) codes

  • General Biochemistry, Genetics and Molecular Biology

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