Alternative splicing in the C-terminal tail ofCav2.1 is essential for preventing a neurological disease in mice

Tomonori Aikawa, Takaki Watanabe, Taisuke Miyazaki, Takayasu Mikuni, Minoru Wakamori, Miyano Sakurai, Hidenori Aizawa, Nobutaka Ishizu, Masahiko Watanabe, Masanobu Kano, Hidehiro Mizusawa, Kei Watase

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Alternative splicing (AS) that occurs at the final coding exon (exon 47) of theCav2.1 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 Cacna1aCtmKO/CtmKO mice developed nonprogressive neurological phenotypes, featuring early-onset ataxia and absence seizure without significant alterations in the basic properties of the channel. Interactions of Cav2.1 withCavβ4 and Rimbp2 were significantly reduced while those with GABAB2 were enhanced in the cerebellum of Cacna1aCtmKO/CtmKO mice. Treatment with the GABAB antagonist CGP35348 partially rescued the motor impairments seen in Cacna1aCtmKO/CtmKO mice. These results suggest that the carboxyl-terminal domain ofCav2.1 is not essential for maintaining the basic properties of the channel in the cerebellar Purkinje neurons but is involved in multiple interactions ofCav2.1 with other proteins, and plays an essential role in preventing a complex neurological disease.

Original languageEnglish
Article numberddx193
Pages (from-to)3094-3104
Number of pages11
JournalHuman molecular genetics
Volume26
Issue number16
DOIs
Publication statusPublished - 2017 Aug 15

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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