The PSD-95/SAP90 family of proteins has recently been implicated in the organization of synaptic structure. Here, we describe the isolation of a novel Ras-GTPase activating protein, SynGAP, that interacts with the PDZ domains of PSD-95 and SAP102 in vitro and in vivo. SynGAP is selectively expressed in brain and is highly enriched at excitatory synapses, where it is present in a large macromolecular complex with PSD95 and the NMDA receptor. SynGAP stimulates the GTPase activity of Ras, suggesting that it negatively regulates Ras activity at excitatory synapses. Ras signaling at the postsynaptic membrane may be involved in the modulation of excitatory synaptic transmission by NMDA receptors and neurotrophins. These results indicate that SynGAP may play an important role in the modulation of synaptic plasticity.
Bibliographical noteFunding Information:
We thank Dr. C. C. Garner for the SAP102 construct, Dr. J. S. Trimmer for the PSD-95 antibody, Drs. A. Lanahan and P. F. Worley for the cDNA libraries and helpful advice on the screening of the libraries, and Drs. K. Kameyama and R. J. O'Brien for invaluable discussion of the work and encouragement. Excellent technical support was provided by C. Doherty, C. Zhang, and J. Bernhardt. We also thank D. Bury for her assistance in preparing the manuscript. This work was supported by the Howard Hughes Medical Institute (R. L. H.) and a training grant (T32NS07368) from the National Institutes of Health (J. H. K.).