論文

査読有り
2017年8月

Alternative splicing in the C-terminal tail of Ca(v)2.1 is essential for preventing a neurological disease in mice

HUMAN MOLECULAR GENETICS
  • Tomonori Aikawa
  • Takaki Watanabe
  • Taisuke Miyazaki
  • Takayasu Mikuni
  • Minoru Wakamori
  • Miyano Sakurai
  • Hidenori Aizawa
  • Nobutaka Ishizu
  • Masahiko Watanabe
  • Masanobu Kano
  • Hidehiro Mizusawa
  • Kei Watase
  • 全て表示

26
16
開始ページ
3094
終了ページ
3104
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1093/hmg/ddx193
出版者・発行元
OXFORD UNIV PRESS

Alternative splicing (AS) that occurs at the final coding exon (exon 47) of the Ca(v)2.1 voltage-gated calcium channel (VGCC) gene produces two major isoforms in the brain, MPI and MPc. These isoforms differ in their splice acceptor sites; human MPI is translated into a polyglutamine tract associated with spinocerebellar ataxia type 6 (SCA6), whereas MPc splices to an immediate stop codon, resulting in a shorter cytoplasmic tail. To gain insight into the functional role of the AS in vivo and whether modulating the splice patterns at this locus can be a potential therapeutic strategy for SCA6, here we created knockin mice that exclusively express MPc by inserting the splice-site mutation. The resultant Cacna1a(CtmKO/CtmKO) mice developed non-progressive neurological phenotypes, featuring early-onset ataxia and absence seizure without significant alterations in the basic properties of the channel. Interactions of Ca(v)2.1 with Ca-v beta 4 and Rimbp2 were significantly reduced while those with GABA(B2) were enhanced in the cerebellum of Cacna1a(CtmKO/CtmKO) mice. Treatment with the GABA(B) antagonist CGP35348 partially rescued the motor impairments seen in Cacna1a(CtmKO/CtmKO) mice. These results suggest that the carboxyl-terminal domain of Ca(v)2.1 is not essential for maintaining the basic properties of the channel in the cerebellar Purkinje neurons but is involved in multiple interactions of Ca(v)2.1 with other proteins, and plays an essential role in preventing a complex neurological disease.

リンク情報
DOI
https://doi.org/10.1093/hmg/ddx193
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/28510727
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000406794000006&DestApp=WOS_CPL
ID情報
  • DOI : 10.1093/hmg/ddx193
  • ISSN : 0964-6906
  • eISSN : 1460-2083
  • PubMed ID : 28510727
  • Web of Science ID : WOS:000406794000006

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