Metabotropic NMDA receptor signaling couples Src family kinases to pannexin-1 during excitotoxicity.
Nat Neurosci
; 19(3): 432-42, 2016 Mar.
Article
in En
| MEDLINE
| ID: mdl-26854804
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Signal Transduction
/
Receptors, N-Methyl-D-Aspartate
/
Connexins
/
Src-Family Kinases
/
Nerve Tissue Proteins
/
Neurons
Limits:
Animals
Language:
En
Journal:
Nat Neurosci
Journal subject:
NEUROLOGIA
Year:
2016
Document type:
Article
Affiliation country:
Canada