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Molecular and Cellular Biology, June 2007, p. 4388-4405, Vol. 27, No. 12
0270-7306/07/$08.00+0 doi:10.1128/MCB.01901-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.
Synaptic Scaffolding Molecule 
Is a Scaffold To Mediate N-Methyl-D-Aspartate Receptor-Dependent RhoA Activation in Dendrites
Junko Iida,1
Hiroyoshi Ishizaki,2
Miki Okamoto-Tanaka,2
Akira Kawata,1
Kazutaka Sumita,1
Shintaro Ohgake,1
Yuji Sato,1
Hiroshi Yorifuji,3
Nobuyuki Nukina,4
Kazumasa Ohashi,5
Kensaku Mizuno,5
Tomonari Tsutsumi,6
Akira Mizoguchi,6
Jun Miyoshi,2
Yoshimi Takai,7 and
Yutaka Hata1*
Department of Medical Biochemistry, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan,1 Department of Molecular Biology, Osaka Medical Center for Cancer and Cardiovascular Disease, Osaka 537-8511, Japan,2 Department of Neuromuscular and Developmental Anatomy, Graduate School of Medicine, Gunma University, 3-39-22 Showa-machi, Maebashi 371-8511, Japan,3 Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Saitama 351-0198, Japan,4 Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Sendai 980-8578, Japan,5 Department of Anatomy, Faculty of Medicine, Mie University, Tsu 514-8507, Japan,6 Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita 565-0871, Japan7
Received 8 October 2006/ Returned for modification 17 November 2006/ Accepted 3 April 2007
Synaptic scaffolding molecule (S-SCAM) interacts with a wide variety of molecules at excitatory and inhibitory synapses. It comprises three alternative splicing variants, S-SCAM
, -ß, and -
. We generated mutant mice lacking specifically S-SCAM. S-SCAM-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-SCAM corrects this abnormal morphology, while S-SCAMß and - 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-SCAM. S-SCAM fails to correct the abnormal spine morphology under the treatment of N-methyl-D-aspartate (NMDA) receptor inhibitor (AP-5), Ca2+/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-SCAM, but not -ß, 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-SCAM is a scaffold required to activate RhoA protein in response to NMDA receptor signaling in dendrites.
* Corresponding author. Mailing address: Department of Medical Biochemistry, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushiima, Bunkyo-ku, Tokyo 113-8519, Japan. Phone: (81) 3 5803 5164. Fax: (81) 3 5803 0121. E-mail: yuhammch{at}tmd.ac.jp
Published ahead of print on 16 April 2007.
Molecular and Cellular Biology, June 2007, p. 4388-4405, Vol. 27, No. 12
0270-7306/07/$08.00+0 doi:10.1128/MCB.01901-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.
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