BioProject

Alternative splicing (AS) that occurs at the final coding exon (exon 47) of the Cav2. More...

Alternative splicing (AS) that occurs at the final coding exon (exon 47) of the Cav2.1 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 its relevance in the pathogenesis of SCA6, here we created knockin mice that exclusively express MPc by inserting the splice-site mutation. The resultant Sca6CtmKO/CtmKO mice developed non-progressive neurological phenotypes resembling those of the Cav4 mutant lethargic (lh/lh), featuring reduced locomotor activity, ataxia and absence seizure without significant alterations in the basic properties of the channel. Interactions of Cav2.1 with Cav4 and Rimbp2 were significantly reduced while those with GABAB2 was enhanced in the cerebellum of Sca6CtmKO/CtmKO mice. Treatment with the GABAB antagonist CGP35348 partially rescued the motor impairments seen in Sca6CtmKO/CtmKO mice. These results suggest that the MPI and MPc-type CaV2.1 channels function in unique Cav2 nano-environments and the carboxyl-terminal domain plays an essential role in the prevention of a complex neurological phenotype. Overall design: We used MPI 118Q/118Q and CtmKO/CtmKO mice at six weeks old in order to investigate spinocerebellar ataxia type 6 (SCA6). Statistical analysis of differently expressed genes was performed using the Linear Models for Microarray Data (limma) package in R/Bioconductor. Less...