| 摘要 |
The invention provides methods of detecting and identifying agents which moduclate the expression or activity of synGAP, a brain-specific Ras/Rap GTPase activating protein. In vivo studies using knock-out and conditional knock-out transgenic animals show that the level of apoptosis in neurons correlates inversely with the level of synGAP protein, indicating that neuronal apoptosis is enhanced by reduction of synGAP. The invention also describes that synGAP is capable of modulating signal transduction pathways associated with the NMDA receptor and triggering apoptosis, including activation of Ras-GAP. Phosphorylation of synGAP by CaMKII increases its Ras GTPase-activating activity by about 70-95%. Moreover, when these and other phosphorylation sites in the synGAP carboxyl tail are mutated, stimulation of GAP activity after phosphorylation is reduced to about 21±5% as compared to about 70-95% for the wild type protein. Also, phosphosite-specific antibodies used to determine levels of synGAP phosphorylation are described herein.
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