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Mol. Biol. Cell 14 (7): 2921-2934

Copyright © 2003 by The American Society for Cell Biology.

p250GAP, a Novel Brain-enriched GTPase-activating Protein for Rho Family GTPases, Is Involved in the N-Methyl-D-aspartate Receptor Signaling

Takanobu Nakazawa *, Ayako M. Watabe {dagger}, Tohru Tezuka *, Yutaka Yoshida *, Kazumasa Yokoyama *, Hisashi Umemori *, Akihiro Inoue {ddagger}, Shigeo Okabe {ddagger}, Toshiya Manabe {dagger} §, and Tadashi Yamamoto * ||

* Division of Oncology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
{dagger} Division of Neuronal Network, Department of Basic Medical Sciences, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
{ddagger} Department of Anatomy and Cell Biology, School of Medicine, Tokyo Medical and Dental University, Tokyo, 113-8519, Japan § Division of Cell Biology and Neurophysiology, Department of Neuroscience, Faculty of Medicine, Kobe University, Kobe 650-0017, Japan

Received for publication September 30, 2002. Revision received March 9, 2003. Accepted for publication March 9, 2003.

Monitoring Editor: Tony Hunter

Abstract: N-Methyl-D-aspartate (NMDA) receptors regulate structural plasticity by modulating actin organization within dendritic spines. Herein, we report identification and characterization of p250GAP, a novel GTPase-activating protein for Rho family proteins that interacts with the GluR{epsilon}2 (NR2B) subunit of NMDA receptors in vivo. The p250GAP mRNA was enriched in brain, with high expression in cortex, corpus striatum, hippocampus, and thalamus. Within neurons, p250GAP was highly concentrated in the postsynaptic density and colocalized with the GluR{epsilon}2 (NR2B) subunit of NMDA receptors and with postsynaptic density-95. p250GAP promoted GTP hydrolysis of Cdc42 and RhoA in vitro and in vivo. When overexpressed in neuroblastoma cells, p250GAP suppressed the activities of Rho family proteins, which resulted in alteration of neurite outgrowth. Finally, NMDA receptor stimulation led to dephosphorylation and redistribution of p250GAP in hippocampal slices. Together, p250GAP is likely to be involved in NMDA receptor activity-dependent actin reorganization in dendritic spines.

Abbreviations used: BAP, bacterial alkaline phosphatase; GAP, GTPase activating protein; GEF, guanine nucleotide exchange factor; GDI, guanine nucleotide dissociation inhibitor; GluR, glutamate receptor; CRIB, Cdc42/Rac-interactive binding domain GST, glutathione S-transferase mAb, monoclonal antibody NMDA, N-methyl-D-aspartate PSD, postsynaptic density RBD, Rho-binding domain SH3, src homology 3.

|| Corresponding author. E-mail address: tyamamot{at}ims.utokyo.ac.jp.

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