| First Author | Zong P | Year | 2024 |
| Journal | Cell Rep | Volume | 43 |
| Issue | 2 | Pages | 113722 |
| PubMed ID | 38308841 | Mgi Jnum | J:349713 |
| Mgi Id | MGI:7613971 | Doi | 10.1016/j.celrep.2024.113722 |
| Citation | Zong P, et al. (2024) TRPM2 enhances ischemic excitotoxicity by associating with PKCgamma. Cell Rep 43(2):113722 |
| abstractText | 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 Cgamma (PKCgamma) association and demonstrate that TRPM2-PKCgamma uncoupling is an effective therapeutic strategy for attenuating NMDAR-mediated excitotoxicity in ischemic stroke. We demonstrate that the TRPM2-PKCgamma interaction allows TRPM2-mediated Ca(2+) influx to promote PKCgamma activation, which subsequently enhances TRPM2-induced potentiation of extrasynaptic NMDAR (esNMDAR) activity. By identifying the PKCgamma binding motif on TRPM2 (M2PBM), which directly associates with the C2 domain of PKCgamma, an interfering peptide (TAT-M2PBM) is developed to disrupt TRPM2-PKCgamma interaction without compromising PKCgamma function. M2PBM deletion or TRPM2-PKCgamma dissociation abolishes both TRPM2-PKCgamma and TRPM2-esNMDAR couplings, resulting in reduced excitotoxic neuronal death and attenuated ischemic brain injury. |
