Molecular and functional diversity of cloned cardiac potassium channels

Action potential duration is an important determinant of refractoriness in cardiac tissue and thus of the ability to propagate electrical impulses. Action potential duration is controlled in part by activation of K+ currents. Block of K+ channels and the resultant prolongation of action potential duration has become an increasingly attractive mode of anti-arrhythmic intervention. Detailed investigation of individual cardiac K+ channels has been hampered by the presence of multiple types of K+ channels in cardiac cells and the difficulty of isolating individual currents. We have approached this problem by employing a combination molecular cloning technology, heterologous channel expression systems, and biophysical analysis of expressed channels. We have focused on six different channels cloned from the rat and human cardiovascular systems. Each channel has unique functional and pharmacological characteristics, and as a group they comprise a series of mammalian K+ channel isoforms that can account for some of the diversity of channels in the mammalian heart. Each channel appears to be encoded by a different gene with little or no evidence for alternate splicing of RNA transcripts to account for the differences in primary amino acid sequence. In addition to the unique kinetic properties of these channel isoforms when expressed as homotetrameric assemblies, the formation of heterotetrameric K+ channels is also observed. The formation of heterotetrameric channels from the different gene products to create new channels with unique kinetic and pharmacological properties might further account for cardiac K+ channel diversity.