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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,
Tohru Tezuka *,
Yutaka Yoshida *,
Kazumasa Yokoyama *,
Hisashi Umemori *,
Toshiya Manabe, and
Tadashi Yamamoto * ||
* Division of Oncology, Department of Cancer Biology, Institute of Medical
Science, University of Tokyo, Tokyo 108-8639, Japan Division of Neuronal Network, Department of Basic Medical Sciences, Institute
of Medical Science, University of Tokyo, Tokyo 108-8639, Japan 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 plasticityby modulating actin organization within dendritic
spines. Herein,we report identification and characterization of p250GAP, a
novel GTPase-activating protein for Rho family proteins thatinteracts with
the GluR2 (NR2B) subunit of NMDA receptors invivo. The p250GAP mRNA was
enriched in brain, with high expressionin cortex, corpus striatum,
hippocampus, and thalamus. Withinneurons, p250GAP was highly concentrated in
the postsynapticdensity and colocalized with the GluR2 (NR2B) subunit
of NMDAreceptors and with postsynaptic density-95. p250GAP promotedGTP
hydrolysis of Cdc42 and RhoA in vitro and in vivo. Whenoverexpressed in
neuroblastoma cells, p250GAP suppressed theactivities of Rho family proteins,
which resulted in alterationof neurite outgrowth. Finally, NMDA receptor
stimulation ledto dephosphorylation and redistribution of p250GAP in
hippocampalslices. Together, p250GAP is likely to be involved in NMDA
receptor activity-dependent actin reorganization in dendriticspines.