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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cell Death / physiology
  • Connexins / metabolism
  • Connexins / physiology*
  • Dizocilpine Maleate / pharmacology
  • Magnesium / pharmacology
  • Membrane Potentials / physiology
  • N-Methylaspartate / pharmacology
  • Nerve Tissue Proteins / metabolism
  • Nerve Tissue Proteins / physiology*
  • Neurons / metabolism
  • Neurons / physiology*
  • Neuroprotective Agents / pharmacology
  • Rats
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Signal Transduction / physiology*
  • Stroke / metabolism
  • Stroke / physiopathology
  • src-Family Kinases / physiology*


  • Connexins
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • Receptors, N-Methyl-D-Aspartate
  • pannexin 1, rat
  • N-Methylaspartate
  • Dizocilpine Maleate
  • src-Family Kinases
  • Magnesium
  • Calcium