Synaptic scaffolding molecule α is a scaffold to mediate N-methyl-D-aspartate receptor-dependent RhoA activation in dendrites

Junko Iida, Hiroyoshi Ishizaki, Miki Okamoto-Tanaka, Akira Kawata, Kazutaka Sumita, Shintaro Ohgake, Yuji Sato, Hiroshi Yorifuji, Nobuyuki Nukina, Kazumasa Ohashi, Kensaku Mizuno, Tomonari Tsutsumi, Akira Mizoguchi, Jun Miyoshi, Yoshimi Takai, Yutaka Hata

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

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-SCAMα, -β, and -γ. We generated mutant mice lacking specifically S-SCAMα. S-SCAMα-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-SCAMα corrects this abnormal morphology, while S-SCAMβ and -γ 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-SCAMα. S-SCAMα 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-SCAMα, but not -β, 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-SCAMα is a scaffold required to activate RhoA protein in response to NMDA receptor signaling in dendrites.

Original languageEnglish
Pages (from-to)4388-4405
Number of pages18
JournalMolecular and cellular biology
Volume27
Issue number12
DOIs
Publication statusPublished - 2007 Jun

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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