Genetic manipulation of cardiac K+ channel function in mice - What have welearned, and where do we go from here?

In the mammalian myocardium, potassium (K+) channels control resting potent ials, action potential waveforms, automaticity, and refractory periods and, in most cardiac cells, multiple types of K+ channels that subserve these f unctions are expressed. Molecular cloning has revealed the presence of a la rge number of K+ channel pore forming (alpha) and accessory (beta) subunits in the heart, and considerable progress has been made recently in defining the relationships between expressed K+ channel subunits and functional car diac K+ channels. To date, more than 20 mouse models with altered K+ channe l expression/functioning have been generated using dominant-negative transg enic and targeted gene deletion approaches. In several instances, the genet ic manipulation of K+ channel subunit expression has revealed the role of s pecific K+ channel subunit subfamilies or individual K+ channel subunit gen es in the generation of myocardial K+ channels. In other cases, however, th e phenotypic consequences have been unexpected. This review summarizes what has been learned from the in situ genetic manipulation of cardiac K+ chann el functioning in the mouse, discusses the limitations of the models develo ped to date, and explores the likely directions of future research.