Ischaemic stroke is a leading cause of adult disability and death. Glutamate plays an essential role in neural development, excitatory synaptic transmission, and plasticity but, during a stroke, glutamate accumulates at synapses, resulting in neuronal death. Excessive influx of Ca2+ ions through N-methyl-D-aspartate (NMDA) glutamate receptors is a major contributor to cell death and brain damage following ischaemic stroke.
So far, directly targeting glutamate receptors has not proved to be an effective way of treating stroke but scientists at the University of Central Florida and Louisiana State University have discovered that uncoupling a kinase from the NR2B subunit of the NMDA receptor blocks damaging Ca2+ influx through the receptor channels and protects neurons against the harmful effects of ischemia. Death-associated protein kinase 1 (DAPK1) is recruited into the NMDA receptor NR2B protein complex during ischaemia and phosphorylates NR2B at Ser-1303, enhancing the NR1/NR2B channel conductance. Genetic deletion of DAPK1 or administration of the peptide, NR2BCT – which blocks the interaction of DAPK1 with the NR2B subunit – protected mice from the damaging effects of cerebral ischaemia. NR2BCT did not affect the catalytic activity of DAPK-1 or the normal physiological functioning of NMDA receptors and the authors hope that, as well as providing new insights into the mechanisms of stroke damage, their discovery will provide a new target for the treatment of stroke which could show advantage over NMDA antagonists.
The study is published in the January 22nd issue of Cell.