Cerebral ischemia results in activation of the
mitogen-activated protein kinase pathway and increased
tyrosine phosphorylation of
proteins associated with postsynaptic densities (PSDs). The authors investigated the possible relation between these events by determining the effect of
ischemia on
tyrosine phosphorylation of the brain-specific, PSD-enriched,
Ras-GTPase activating
protein, SynGAP. Transient (15 minutes) global
ischemia was produced in rats by 4-vessel occlusion and PSDs prepared from forebrains immediately after
ischemia or at 20 minutes, 1 hour, or 24 hours of reperfusion.
Tyrosine phosphorylation of SynGAP was elevated relative to
sham-operated controls by 20 minutes of reperfusion and remained elevated for at least 24 hours.
Tyrosine phosphorylation of SynGAP also increased in CA1 and CA3/DG subfields of the hippocampus. Enhanced
tyrosine phosphorylation of SynGAP was not accompanied by a change in PSD RasGAP activity. SynGAP bound to the SH2 domains of Src and Fyn in a
tyrosine phosphorylation-dependent fashion, and this interaction increased after
ischemia. SynGAP binds to the PDZ domains of PSD-95/SAP90 and coimmunoprecipitated with PSD-95. The coimmunoprecipitation of SynGAP with PSD-95 decreased after
ischemia. The results indicate that changes in the properties and interactions of SynGAP may be involved in the neuropathology of
ischemia.