ABSTRACT
Genomes contain a finite number of genes, with ion channels comprising ~1% of the human genome. This limited genetic code must produce a vast diversity of protein function that spans developmental programs to tissue-specific tuning of physiological function. A ubiquitous mechanism for creating this diversity is alternative splicing of mRNA, producing a multitude of unique transcripts encoded by a single gene. Alternative splicing results in addition, deletion or modification of protein modules, arising from independent regulation of discrete functional domains or coordinate regulation of functionally interconnected domains. Ion channel exon variation can lead to incremental transitions in current properties or create binary regulatory switching, detectable by highly sensitive electrophysiological methods. Splice variants exhibit divergent gating properties, allosteric modulation, permeability, regulation by signaling pathways, expression and localization. Alternative splicing of ion channels is particularly prevalent in the brain, where their functional complexity is most elaborate. Tailoring channel properties by alternative splicing enables the intricate fine-tuning of ionic networks underlying excitability and homeostasis, vastly expanding the parameter space for physiological solutions when amplified across the repertoire of ion channels expressed within a cell or tissue.
