The PDZ domain-containing proteins, such as PSD-95 and GRIP, have been suggested to be involved in the targeting of glutamate receptors, a process that plays a critical role in the efficiency of synaptic transmission and plasticity. To address the molecular mechanisms underlying AMPA receptor synaptic localization, we have identified several GRIP-associated proteins (GRASPs) that bind to distinct PDZ domains within GRIP. GRASP-1 is a neuronal rasGEF associated with GRIP and AMPA receptors in vivo. Overexpression of GRASP-1 in cultured neurons specifically reduced the synaptic targeting of AMPA receptors. In addition, the subcellular distribution of both AMPA receptors and GRASP-1 was rapidly regulated by the activation of NMDA receptors. These results suggest that GRASP-1 may regulate neuronal ras signaling and contribute to the regulation of AMPA receptor distribution by NMDA receptor activity.
Bibliographical noteFunding Information:
We thank Haining Zhong and Marianne Kulesa for assistance with the yeast two-hybrid screening and Dr. Morgan Sheng for providing anti-GRIP1 antibody that was used for coimmunoprecipitation from cultured neuron lysates. We would also like to thank Doreen Bury for editorial assistance and Dr. David Ginty, Dr. Robert Scannevin, and Dr. Bernard McDonald for critical reading of the manuscript. This work was supported by the Howard Hughes Medical Institute and the National Institutes of Health (National Institute of Neurological Disorders and Stroke).
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