Changing stroke rehab and research worldwide now.Time is Brain! trillions and trillions of neurons that DIE each day because there are NO effective hyperacute therapies besides tPA(only 12% effective). I have 523 posts on hyperacute therapy, enough for researchers to spend decades proving them out. These are my personal ideas and blog on stroke rehabilitation and stroke research. Do not attempt any of these without checking with your medical provider. Unless you join me in agitating, when you need these therapies they won't be there.

What this blog is for:

My blog is not to help survivors recover, it is to have the 10 million yearly stroke survivors light fires underneath their doctors, stroke hospitals and stroke researchers to get stroke solved. 100% recovery. The stroke medical world is completely failing at that goal, they don't even have it as a goal. Shortly after getting out of the hospital and getting NO information on the process or protocols of stroke rehabilitation and recovery I started searching on the internet and found that no other survivor received useful information. This is an attempt to cover all stroke rehabilitation information that should be readily available to survivors so they can talk with informed knowledge to their medical staff. It lays out what needs to be done to get stroke survivors closer to 100% recovery. It's quite disgusting that this information is not available from every stroke association and doctors group.

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
left
  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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