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Nat Neurosci. 2016 Mar;19(3):432-42. doi: 10.1038/nn.4236. Epub 2016 Feb 8.

Metabotropic NMDA receptor signaling couples Src family kinases to pannexin-1 during excitotoxicity.

Author information

1
Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
2
Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
3
Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada.
4
Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Abstract

Overactivation of neuronal N-methyl-D-aspartate receptors (NMDARs) causes excitotoxicity and is necessary for neuronal death. In the classical view, these ligand-gated Ca(2+)-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 Mg(2+) or a Ca(2+)-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.

PMID:
26854804
DOI:
10.1038/nn.4236
[Indexed for MEDLINE]

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