Direct interaction between GluR2 and GAPDH regulates AMPAR-mediated excitotoxicity
1 Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, Canada
2 Brain Research Center, University of British Columbia, Vancouver, Canada
3 Department of Psychiatry, University of Toronto, Toronto, Canada
4 Department of Neuroscience, Centre for Addiction and Mental Health, Clarke Division, 250 College Street, Toronto, ON, M5T 1R8, Canada
Molecular Brain 2012, 5:13 doi:10.1186/1756-6606-5-13Published: 26 April 2012
Over-activation of AMPARs (α−amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptors) is implicated in excitotoxic neuronal death associated with acute brain insults, such as ischemic stroke. However, the specific molecular mechanism by which AMPARs, especially the calcium-impermeable AMPARs, induce neuronal death remains poorly understood. Here we report the identification of a previously unrecognized molecular pathway involving a direct protein-protein interaction that underlies GluR2-containing AMPAR-mediated excitotoxicity. Agonist stimulation of AMPARs promotes GluR2/GAPDH (glyceraldehyde-3-phosphate dehydrogenase) complex formation and subsequent internalization. Disruption of GluR2/GAPDH interaction by administration of an interfering peptide prevents AMPAR-mediated excitotoxicity and protects against damage induced by oxygen-glucose deprivation (OGD), an in vitro model of brain ischemia.