Genetic manipulation of cardiac K(+) channel function in mice: what have we learned, and where do we go from here?
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 (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 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.
Nerbonne
J M
JM
Department of Molecular Biology, Washington University Medical School, St Louis, MO, USA.
Nichols
C G
CG
Schwarz
T L
TL
Escande
D
D
D000200:Action Potentials; D000818:Animals; D051668:Delayed Rectifier Potassium Channels; D004195:Disease Models, Animal; D004553:Electric Conductivity; D005544:Forecasting; D006321:Heart / Q000502:physiology*; D006331:Heart Diseases / Q000209:etiology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015221:Potassium Channels / Q000235:genetics* / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000502:physiology
D051668:Delayed Rectifier Potassium Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D024642:Potassium Channels, Voltage-Gated