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
- 巻
- 26
- 号
- 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
- ID情報
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- DOI : 10.1093/hmg/ddx193
- ISSN : 0964-6906
- eISSN : 1460-2083
- PubMed ID : 28510727
- Web of Science ID : WOS:000406794000006