Alternative Splicing and CaV-Associated Channelopathies

Voltage-gated calcium channels (VGCCs) are multi-subunit ion channel proteins that control and regulate a wide array of physiological processes. Their dysfunction has been implicated in several neurological, cardiac, psychiatric, endocrine, oncogenic, and muscular disorders. The diverse and specialized cellular functions involving VGCC-mediated calcium signaling stem from two primary mechanisms: differential and cell-specific expression of pore-forming (α1) and auxiliary subunit genes, and extensive alternative splicing of their pre-mRNA. All the 10 α1-encoding genes undergo alternative splicing to generate a wide array of cell-specific CaV variants with distinct biophysical, pharmacological, and protein-protein interaction properties. This proteomic diversity and the associated cell-specific expression signature of CaV splice variants are tightly regulated by trans-acting splicing factors-RNA-binding proteins that control the inclusion or skipping of alternatively spliced exons during post-transcriptional pre-mRNA processing. The discovery that several channelopathies are caused by aberrant splicing due to genetic mutations in either cis-acting binding elements on the pre-mRNA or in core splicing machinery components highlights the crucial role of alternative splicing in VGCC-related pathologies. These insights have opened new therapeutic avenues, as targeting the alternative splicing of disease-associated specific exons has recently emerged as a novel, promising treatment for neurodevelopmental disorders and channelopathies associated with splicing dysfunction.