ABSTRACT
Genomes contain a nite number of genes. Yet this limited genetic code must produce a vast diversity of protein function that spans developmental programs to tissue-specic tuning of physiological function. A fundamental and nearly ubiquitous genetic 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 alteration of functional protein modules, arising from independent regulation of discrete functional domains (Raingo et al., 2007) or coordinate regulation of functionally interconnected domains (Glauser et al., 2011; Johnson et al., 2011). In ion channels, exon variation can lead to incremental transitions in current properties or create on-/off-type regulatory switching (Lipscombe et al., 2009). Electrophysiological recordings of ionic currents have proven to be a particularly sensitive detection method for the functional consequences of alternative splicing. Ion channel splice variants exhibit dierent gating properties, allosteric modulation, permeability, regulation by signaling pathways, and expression and localization. Alternative splicing is particularly prevalent in the brain, where the complexities of ion channel function are most elaborate. Tailoring of ion channel properties by alternative splicing enables intricate ne-tuning of the ionic networks underlying excitabi lity and homeostasis, vastly expanding the parameter space for physiological solutions when amplied across the repertoire of ion channels expressed within a cell or tissue.
