Disruption of the GluR2-NSF interaction protects primary hippocampal neurons from ischemic stress.
A specific interaction between the AMPA receptor subunits GluR2 and GluR3 and the fusion protein NSF has recently been identified. Disruption of this interaction by adenoviral-mediated expression of a peptide (pep2m) corresponding to the NSF-binding region of GluR2 results in a dramatic reduction in surface expression of AMPA receptors in primary hippocampal neurons. Here we report that expression of pep2m from a recently developed neuronal-specific adenoviral system gave significant neuroprotection to primary CA1-CA3 hippocampal neurons following stimulation with kainate (KA) and this was accompanied by a reduction in Ca(2+) influx. Protection was also observed following glucose deprivation and exposure to ischemic buffer in the absence of any NMDA receptor antagonists. These results provide strong evidence that AMPA receptors play a direct role in mediating postischemic neurotoxicity.
Ralph
G S
GS
Division of Medicine, University of Bristol, Marlborough Street, Bristol, BS2 8HW.
Bienemann
A
A
Ma
J
J
Tan
H K
HK
Noel
J
J
Henley
J M
JM
Uney
J B
JB
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D005947:Glucose; D006624:Hippocampus / Q000166:cytology; D007608:Kainic Acid / Q000633:toxicity; D052066:N-Ethylmaleimide-Sensitive Proteins; D009410:Nerve Degeneration / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D033921:Vesicular Transport Proteins
D002352:Carrier Proteins; D018690:Excitatory Amino Acid Agonists; D018091:Receptors, AMPA; D011994:Recombinant Proteins; D033921:Vesicular Transport Proteins; D052066:N-Ethylmaleimide-Sensitive Proteins; D005947:Glucose; C104722:glutamate receptor ionotropic, AMPA 2; D007608:Kainic Acid; D002118:Calcium