title: Metabotropic NMDA receptor signaling couples Src family kinases to pannexin-1 during excitotoxicity.
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.
authors: Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.|Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors: Nicholas L
authors: NL
authors: Weilinger
authors: Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.|Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors: Alexander W
authors: AW
authors: Lohman
authors: Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors: Brooke D
authors: BD
authors: Rakai
authors: Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.|Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors: Evelyn M M
authors: EM
authors: Ma
authors: Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors: Jennifer
authors: J
authors: Bialecki
authors: Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors: Valentyna
authors: V
authors: Maslieieva
authors: Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors: Travis
authors: T
authors: Rilea
authors: Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada.
authors: Mischa V
authors: MV
authors: Bandet
authors: Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada.
authors: Nathan T
authors: NT
authors: Ikuta
authors: Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.|Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors: Lucas
authors: L
authors: Scott
authors: Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.|Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors: Michael A
authors: MA
authors: Colicos
authors: Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.|Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors: G Campbell
authors: GC
authors: Teskey
authors: Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada.
authors: Ian R
authors: IR
authors: Winship
authors: Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.|Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors: Roger J
authors: http://orcid.org/0000-0002-7019-7246
authors: RJ
authors: Thompson
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D017630:Connexins / Q000378:metabolism / Q000502:physiology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D008274:Magnesium / Q000494:pharmacology; D008564:Membrane Potentials / Q000502:physiology; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D020521:Stroke / Q000378:metabolism / Q000503:physiopathology; D019061:src-Family Kinases / Q000502:physiology*
chemical_list: D017630:Connexins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; C479936:pannexin 1, rat; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D019061:src-Family Kinases; D008274:Magnesium; D002118:Calcium