Synaptic scaffolding molecule alpha is a scaffold to mediate N-methyl-D-aspartate receptor-dependent RhoA activation in dendrites.
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.
Iida
Junko
J
Department of Medical Biochemistry, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushiima, Tokyo, Japan.
Ishizaki
Hiroyoshi
H
Okamoto-Tanaka
Miki
M
Kawata
Akira
A
Sumita
Kazutaka
K
Ohgake
Shintaro
S
Sato
Yuji
Y
Yorifuji
Hiroshi
H
Nukina
Nobuyuki
N
Ohashi
Kazumasa
K
Mizuno
Kensaku
K
Tsutsumi
Tomonari
T
Mizoguchi
Akira
A
Miyoshi
Jun
J
Takai
Yoshimi
Y
Hata
Yutaka
Y
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*
D020033:Protein Isoforms; D016194:Receptors, N-Methyl-D-Aspartate; D020742:rhoA GTP-Binding Protein