Genetic Manipulation of Cardiac K Channel Function in Mice

In the mammalian myocardium, potassium (K ) channels control resting potentials, action potential waveforms, automaticity, and refractory periods and, in most cardiac cells, multiple types of K channels that subserve these functions are expressed. Molecular cloning has revealed the presence of a large number of K channel pore forming ( ) and accessory ( ) subunits in the heart, and considerable progress has been made recently in defining the relationships between expressed K channel subunits and functional cardiac K channels. To date, more than 20 mouse models with altered K channel expression/functioning have been generated using dominant-negative transgenic and targeted gene deletion approaches. In several instances, the genetic manipulation of K channel subunit expression has revealed the role of specific K channel subunit subfamilies or individual K channel subunit genes in the generation of myocardial K channels. In other cases, however, the phenotypic consequences have been unexpected. This review summarizes what has been learned from the in situ genetic manipulation of cardiac K channel functioning in the mouse, discusses the limitations of the models developed to date, and explores the likely directions of future research. (Circ Res. 2001; 89:944-956.)