Evolution of the Human Ion Channel Set

Ion channels are intimately involved in virtually every physiological process of consequence in humans. Their importance is underscored by the identification of numerous “channelopathies”, human diseases caused by ion channel mutations. Ion Channels have consequently been viewed as fertile ground for drug discovery and, indeed, they represent one of the largest target classes for current medicines. The future prospects of ion channels as a target class are tied to the functional characterization of the human ion channel set on a genomic scale. The focus of this review is to describe the molecular diversity and conservation of human ion channels. The human genome contains at least 232 genes that encode the pore-forming subunits of plasma membrane ion channels. Comparative genome analysis shows that most human ion channel gene families have their origins in the earliest metazoans but the human genes are largely derived from duplications that took place in the vertebrate lineage. The mouse and human ion channel gene sets are virtually identical, but differ significantly from fish channel sets. Genome comparisons highlight a number of highly conserved channel families that do not yet have specifically defined functional roles in vivo. These channel families are likely to have non-redundant functions in metazoans and represent some of the best new opportunities for channel target prospecting. Furthermore, genome- wide patterns of sequence conservation can now be used to refine strategies for the identification of gene-specific channel probes.