期刊
NATURE NEUROSCIENCE
卷 19, 期 3, 页码 432-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.4236
关键词
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资金
- Canadian Institutes for Health Research (CIHR) [136812, 110967, 201022, 130495]
- Alberta Innovates-Health Solutions (AI-HS)
- Canadian Foundation for Innovation
- Natural Sciences and Engineering Research Council of Canada
- AI-HS
- Cumming School of Medicine via the Ronald and Irene Ward Foundation
- Gwendolyn McLean Fund
- Hotchkiss Brain Institute
- CIHR
- Alberta Innovates [201400500] Funding Source: researchfish
Overactivation of neuronal N-methyl-d-aspartate receptors (NMDARs) causes excitotoxicity and is necessary for neuronal death. In the classical view, these ligand-gated Ca2+-permeable ionotropic receptors require co-agonists and membrane depolarization for activation. We report that NMDARs signal during ligand binding without activation of their ion conduction pore. Pharmacological pore block with MK-801, physiological pore block with Mg2+ or a Ca2+-impermeable NMDAR variant prevented NMDAR currents, but did not block excitotoxic dendritic blebbing and secondary currents induced by exogenous NMDA. NMDARs, Src kinase and Panx1 form a signaling complex, and activation of Panx1 required phosphorylation at Y308. Disruption of this NMDAR-Src-Panx1 signaling complex in vitro or in vivo by administration of an interfering peptide either before or 2 h after ischemia or stroke was neuroprotective. Our observations provide insights into a new signaling modality of NMDARs that has broad-reaching implications for brain physiology and pathology.
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