Recent Advances in Therapeutic Strategies That Focus on the Regulation of Ion Channel Expression

A number of different ion channel types are involved in cell signaling networks, and homeostatic regulatory mechanisms contribute to the control of ion channel expression. Profiling of global gene expression using microarray technology has recently provided novel insights into the molecular mechanisms underlying the homeostatic and pathological control of ion channel expression. It has demonstrated that the dysregulation of ion channel expression is associated with the pathogenesis of neural, cardiovascular, and immune diseases as well as cancers. In addition to the transcriptional, translational, and post-translational regulation of ion channels, potentially important evidence on the mechanisms controlling ion channel expression has recently been accumulated. The regulation of alternative pre-mRNA splicing is therefore a novel therapeutic strategy for the treatment of dominant-negative splicing disorders. Epigenetic modification plays a key role in various pathological conditions through the regulation of pluripotency genes. Inhibitors of pre-mRNA splicing and histone deacetyalase/methyltransferase have potential as potent therapeutic drugs for cancers and autoimmune and inflammatory diseases. Moreover, membrane-anchoring proteins, lysosomal and proteasomal degradation-related molecules, auxiliary subunits, and pharmacological agents alter the protein folding, membrane trafficking, and post-translational modifications of ion channels, and are linked to expression-defect channelopathies. In this review, we focused on recent insights into the transcriptional, spliceosomal, epigenetic, and proteasomal regulation of ion channel expression: Ca(2+) channels (TRPC/TRPV/TRPM/TRPA/Orai), K(+) channels (voltage-gated, KV/Ca(2+)-activated, KCa/two-pore domain, K2P/inward-rectifier, Kir), and Ca(2+)-activated Cl(-) channels (TMEM16A/TMEM16B). Furthermore, this review highlights expression of these ion channels in expression-defect channelopathies.