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

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. [Display omitted] •TRPM2 physically and functionally interacts with extrasynaptic NMDAR•TRPM2-NMDAR interaction exacerbates excitotoxicity during ischemic stroke•TRPM2 recruits PKCγ, thereby increasing NMDAR’s surface expression•Uncoupling TRPM2-NMDAR interaction attenuates ischemic brain injury Zong et al. discover an unexpected association between the oxidative stress-sensitive ion channel TRPM2 and the extrasynaptic NMDA receptor (NMDAR) in the neurons, which enhances excitotoxicity during ischemic brain injury. Neuron-specific knockout of TRPM2 or uncoupling of the TRPM2-NMDAR association using an interfering peptide protects mice against ischemic stroke.