Document Type

Article

Publication Date

2-27-2024

Keywords

JGM, Humans, Protein Kinases, TRPM Cation Channels, Receptors, N-Methyl-D-Aspartate, Peptides, Brain Injuries

ISSN

2211-1247

PMID

38308841

DOI

https://doi.org/10.1016/j.celrep.2024.113722

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 Cg (PKCg) as- sociation and demonstrate that TRPM2-PKCg uncoupling is an effective therapeutic strategy for attenuating NMDAR-mediated excitotoxicity in ischemic stroke. We demonstrate that the TRPM2-PKCg interaction al- lows TRPM2-mediated Ca2+ influx to promote PKCg activation, which subsequently enhances TRPM2- induced potentiation of extrasynaptic NMDAR (esNMDAR) activity. By identifying the PKCg binding motif on TRPM2 (M2PBM), which directly associates with the C2 domain of PKCg, an interfering peptide (TAT- M2PBM) is developed to disrupt TRPM2-PKCg interaction without compromising PKCg function. M2PBM deletion or TRPM2-PKCg dissociation abolishes both TRPM2-PKCg and TRPM2-esNMDAR couplings, re- sulting in reduced excitotoxic neuronal death and attenuated ischemic brain injury.

Comments

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

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