Alternative splicing of voltage-gated calcium channels: from molecular biology to disease

Recent developments in the diversification of voltage-gated calcium channel function center on the rapidly emerging role of the posttranscriptional mechanism of alternative splicing. A number of diseases have been found to relate to the dysfunction of alternatively spliced exons arising from either genetic mutations or alterations in the splicing machinery. Mutations in some genes associated with congenital diseases have been detected to reside in alternatively spliced exons. As such, the severity of tissue-selective pathology of the disease will depend on the level of expression of the alternatively spliced exons in that tissue, as well as the extent in the change in channel properties. Importantly, alteration in channel properties is affected by the backbone array of the combinatorial alternatively spliced exons within the channel. In other words, the context by which mutations or alternatively spliced exons are expressed is a great influence on the alteration of channel properties and as such physiology and disease. We reviewed here recent comprehension of alternative splicing of voltage-gated calcium channels and how such structural and functional diversity of voltage-gated calcium channels will aid to clarify the pathophysiology of relevant diseases. Such understandings will further provide guidance for novel treatment.