MOLECULAR AND FUNCTIONAL DIVERSITY OF CLONED CARDIAC POTASSIUM CHANNELS

Action potential duration is an important determinant of refractorines s in cardiac tissue and thus of the ability to propagate electrical im pulses. 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 antiarrhythmic intervention. Detailed investigation of individual c ardiac K+ channels has been hampered by the presence of multiple types of K+ channels in cardiac cells and the difficulty of isolating indiv idual currents. We have approached this problem by employing a combina tion molecular cloning technology, heterologous channel expression sys tems, 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 chara cteristics, and is a group they comprise a series of mammalian K+ chan nel isoforms that can account for some of the diversity of channels in the mammalian heart. Each channel appears to be encoded by a differen t gene with little or no evidence for alternate splicing of RNA transc ripts to account for the differences in primary amino acid sequence. I n addition to the unique kinetic properties of these channel isoforms when expressed as homotetrameric assemblies, the formation of heterote trameric K+ channels is also observed. The formation of heterotetramer ic channels from the different gene products to create new channels wi th unique kinetic and pharmacological properties might further account for cardiac K+ channel diversity.