Molecular and functional diversity of K+ channels

1. Amino acid sequences encoding K+ channels belong to several subfamilies of the voltage-gated ion channel superfamily which includes Na2+-, Ca2+-, and cyclic nucleotide gated channels. The Kv family is the largest group, and encodes delayed rectifier, A-type, and large conductance Ca2+ activated K+ channels. 2. The alpha-subunits of Kv channels form as tetramers of four independent subunits. Each subunit has six membrane spanning regions and a pore forming 'P' region. Subunits belong to subfamilies (Kv1-4, BK, Eag) comprising multiple members, each of which has distinct properties resembling each of the major types of native Kv channel when expressed as homomultimers in heterologous systems. 3. Enormous diversity of Kv channel function arises from the multiplicity of subunits, the formation of heteromultimers within subfamilies and from association with intracellular beta-subunit proteins. 4. In the absence of direct structural information, mutational analyses have provided considerable insights into the structure of the voltage-sensor, pore-forming region and the sites of action of drugs, toxins and associated proteins. 5. Another subfamily, the inwardly rectifying, or KIR, family, appears to have arisen from a deletion of the first four membrane spanning regions of ancient Kv channels, changing gating properties from outward to inward rectification. These include the G-protein gated inward rectifiers and KATP channels.