Thursday, February 11, 2016

Metabotropic NMDA receptor signaling couples Src family kinases to pannexin-1 during excitotoxicity - hyperacute saving of neurons

Stopping one of the causes of neuronal death.
Video TV report on this here:
http://calgary.ctvnews.ca/video?clipId=806097&binId=1.1201914&playlistPageNum=1#_gus&_gucid=&_gup=twitter&_gsc=mRhfBfW

The research here:
http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.4236.html
Nature Neuroscience
doi:10.1038/nn.4236
Received
Accepted
Published online

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 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.

Subject terms:

At a glance

Figures

First | 1-3 of 17 | Last
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  1. NMDA-induced dendritic blebbing is differentially blocked by noncompetitive and competitive antagonists.
    Figure 1
  2. Disrupting NMDA ligand binding blocks the secondary current.
    Figure 2
  3. NMDA-induced ionic dysregulation occurs during pore block by physiological Mg2+.
    Figure 3
  4. NMDAR-Src-Panx1 colocalize in a metabotropic signaling complex.
    Figure 4
  5. Activation of NMDAR-Src-Panx1 signaling during excitotoxicity requires phosphorylation of Src and Panx1.
    Figure 5
  6. Disrupting metabotropic NMDAR signaling prevented Panx1-mediated Ca2+ dysregulation, MPT and neuronal death during in vitro ischemia.
    Figure 6
  7. Blocking the NMDAR metabotropic signalsome reduces lesion size and sensorimotor deficits induced by stroke in vivo.
    Figure 7
  8. Acute Block of Panx1 does not inhibit NMDAR currents.
    Supplementary Fig. 1
  9. Activation of Excitotoxic Panx1 currents requires both ligand binding sites of NMDARs.
    Supplementary Fig. 2
  10. Pre-blocked NMDARs signal metabotropically to Panx1 during excitotoxicity.
    Supplementary Fig. 3
  11. GluN1 N616R pore mutation renders NMDARs Ca2+-impermeable.
    Supplementary Fig. 4
  12. NMDAR activation induces Panx1 phosphorylation at tyrosine 308.
    Supplementary Fig. 5
  13. Src mediated phosphorylation of Panx1 is Ca2+-independent.
    Supplementary Fig. 6
  14. TAT-Panx308 is a specific inhibitor of Src-mediated activation of Panx1.
    Supplementary Fig. 7
  15. Panx1 opening in the plasma membrane induces mitochondrial dysfunction during ischemia.
    Supplementary Fig. 8
  16. TAT-Panx308 does not alter cerebral blood flow under physiological conditions.
    Supplementary Fig. 9
  17. Full length blots cropped for representative figures.
    Supplementary Fig. 10
right
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