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
Affiliations
Pengyu Zong
Department of Cell Biology, Calhoun Cardiology Center, University of Connecticut School of Medicine (UConn Health), Farmington, CT 06030, USA; Institute for the Brain and Cognitive Sciences, University of Connecticut, 337 Mansfield Road, Unit 1272, Storrs, CT 06269, USA
Jianlin Feng
Department of Cell Biology, Calhoun Cardiology Center, University of Connecticut School of Medicine (UConn Health), Farmington, CT 06030, USA
Nicholas Legere
The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA; Department of Genetics and Genome Sciences, UConn Health, Farmington, CT 06030, USA
Yunfeng Li
Department of Molecular Biology and Biophysics, University of Connecticut School of Medicine (UConn Health), Farmington, CT 06030, USA
Zhichao Yue
Department of Cell Biology, Calhoun Cardiology Center, University of Connecticut School of Medicine (UConn Health), Farmington, CT 06030, USA
Cindy X. Li
Department of Cell Biology, Calhoun Cardiology Center, University of Connecticut School of Medicine (UConn Health), Farmington, CT 06030, USA; Institute for the Brain and Cognitive Sciences, University of Connecticut, 337 Mansfield Road, Unit 1272, Storrs, CT 06269, USA
Yasuo Mori
Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan
Barbara Miller
Departments of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, P.O. Box 850, Hershey, PA 17033, USA
Bing Hao
Department of Molecular Biology and Biophysics, University of Connecticut School of Medicine (UConn Health), Farmington, CT 06030, USA
Lixia Yue
Department of Cell Biology, Calhoun Cardiology Center, University of Connecticut School of Medicine (UConn Health), Farmington, CT 06030, USA; Corresponding author
Summary: 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.
