Rho-GAP Actin' at NMDA Receptor

Science's STKE  22 Jul 2003:
Vol. 2003, Issue 192, pp. tw283-TW283
DOI: 10.1126/stke.2003.192.tw283

Physical changes in synapses of neurons in the brain are thought to allow long-term storage of information and to provide molecular mechanisms that contribute to the processes of learning and memory. Changes in the actin cytoskeleton are associated with receptor-induced structural alterations in dendritic spines of postsynaptic neurons and are regulated by the small GTPases (guanosine triphosphatases) Rac and Rho. Now, in a hunt for proteins that physically interact with the NMDA (N-methyl-D-aspartate) receptor GluRϵ2 subunit, Nakazawa et al. have identified a protein with sequence similarity to GTPase-activating proteins (GAPs) that they call p250GAP. The p250GAP protein showed GAP activity toward the Rho-family GTPases RhoA and Cdc42 both in vitro and in transfected cells. Immunofluorescence microscopy and cell fractionation showed p250GAP to be concentrated in postsynaptic densities and localized near NMDA receptors. In Neuro-2A neuroblastoma cells in culture, overexpression of p250GAP either promoted or inhibited neurite outgrowth, depending on whether serum was or was not present. Treatment of cultures of hippocampal slices from mouse brain with NMDA appeared to cause dephosphorylation of p250GAP and to cause release of p250GAP from synaptic complexes. Such modulation could provide a mechanism for local remodeling of particular synaptic spines in which the NMDA receptor has been activated and might thereby contribute to generation of synaptic plasticity.

T. Nakazawa, A. M. Watabe, T. Tezuka, Y. Yoshida, K. Yokoyama, H. Umemori, A. Inoue, S. Okabe, T. Manabe, T. Yamamoto, p250GAP, a novel brain-enriched GTPase-activating protein for Rho family GTPases, is involved in the N-methyl-D-aspartate receptor signaling. Mol. Biol. Cell 14, 2921-2934 (2003). [Abstract] [Full Text]