title: p250GAP, a novel brain-enriched GTPase-activating protein for Rho family GTPases, is involved in the N-methyl-d-aspartate receptor signaling.
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 GluRepsilon2 (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 GluRepsilon2 (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.
authors.affiliation: Division of Oncology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Nakazawa
authors.forename: Ayako M
authors.initials: AM
authors.lastname: Watabe
authors.forename: Tohru
authors.initials: T
authors.lastname: Tezuka
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Yokoyama
authors.forename: Hisashi
authors.initials: H
authors.lastname: Umemori
authors.forename: Akihiro
authors.initials: A
authors.lastname: Inoue
authors.forename: Shigeo
authors.initials: S
authors.lastname: Okabe
authors.forename: Toshiya
authors.initials: T
authors.lastname: Manabe
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamamoto
mesh_terms: D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D020690:GTPase-Activating Proteins / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D016501:Neurites / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction; D020798:Two-Hybrid System Techniques; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; D020690:GTPase-Activating Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein