title: Synaptic scaffolding molecule alpha is a scaffold to mediate N-methyl-D-aspartate receptor-dependent RhoA activation in dendrites.
abstract: Synaptic scaffolding molecule (S-SCAM) interacts with a wide variety of molecules at excitatory and inhibitory synapses. It comprises three alternative splicing variants, S-SCAMalpha, -beta, and -gamma. We generated mutant mice lacking specifically S-SCAMalpha. S-SCAMalpha-deficient mice breathe and feed normally but die within 24 h after birth. Primary cultured hippocampal neurons from mutant mice have abnormally elongated dendritic spines. Exogenously expressed S-SCAMalpha corrects this abnormal morphology, while S-SCAMbeta and -gamma have no effect. Active RhoA decreases in cortical neurons from mutant mice. Constitutively active RhoA and ROCKII shift the length of dendritic spines toward the normal level, whereas ROCK inhibitor (Y27632) blocks the effect by S-SCAMalpha. S-SCAMalpha fails to correct the abnormal spine morphology under the treatment of N-methyl-d-aspartate (NMDA) receptor inhibitor (AP-5), Ca(2+)/calmodulin kinase inhibitor (KN-62), or tyrosine kinase inhibitor (PP2). NMDA treatment increases active RhoA in dendrites in wild-type hippocampal neurons, but not in mutant neurons. The ectopic expression of S-SCAMalpha, but not -beta, recovers the NMDA-responsive accumulation of active RhoA in dendrites. Phosphorylation of extracellular signal-regulated kinase 1/2 and Akt and calcium influx in response to NMDA are not impaired in mutant neurons. These data indicate that S-SCAMalpha is a scaffold required to activate RhoA protein in response to NMDA receptor signaling in dendrites.
authors: Department of Medical Biochemistry, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushiima, Tokyo, Japan.
authors: Junko
authors: J
authors: Iida
authors: Hiroyoshi
authors: H
authors: Ishizaki
authors: Miki
authors: M
authors: Okamoto-Tanaka
authors: Akira
authors: A
authors: Kawata
authors: Kazutaka
authors: K
authors: Sumita
authors: Shintaro
authors: S
authors: Ohgake
authors: Yuji
authors: Y
authors: Sato
authors: Hiroshi
authors: H
authors: Yorifuji
authors: Nobuyuki
authors: N
authors: Nukina
authors: Kazumasa
authors: K
authors: Ohashi
authors: Kensaku
authors: K
authors: Mizuno
authors: Tomonari
authors: T
authors: Tsutsumi
authors: Akira
authors: A
authors: Mizoguchi
authors: Jun
authors: J
authors: Miyoshi
authors: Yoshimi
authors: Y
authors: Takai
authors: Yutaka
authors: Y
authors: Hata
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D003712:Dendrites / Q000378:metabolism*; D049229:Dendritic Spines / Q000473:pathology; D018274:Electroporation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D011247:Pregnancy; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D011995:Recombination, Genetic; D013569:Synapses / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D016194:Receptors, N-Methyl-D-Aspartate; D020742:rhoA GTP-Binding Protein