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pubmed:abstractText |
1. Ventricular myocytes demonstrate a steeply inwardly rectifying K(+) current termed I(K1). We investigated the molecular basis for murine I(K1) by removing the genes encoding Kir2.1 and Kir2.2. The physiological consequences of the loss of these genes were studied in newborn animals because mice lacking Kir2.1 have a cleft palate and die shortly after birth. 2. Kir2.1 (-/-) ventricular myocytes lack detectable I(K1) in whole-cell recordings in 4 mM external K(+). In 60 mM external K(+) a small, slower, residual current is observed. Thus Kir2.1 is the major determinant of I(K1). Sustained outward K(+) currents and Ba(2+) currents through L- and T-type channels were not significantly altered by the mutation. A 50 % reduction in I(K1) was observed in Kir2.2 (-/-) mice, raising the possibility that Kir2.2 can also contribute to the native I(K1). 3. Kir2.1 (-/-) myocytes showed significantly broader action potentials and more frequent spontaneous action potentials than wild-type myocytes. 4. In electrocardiograms of Kir2.1 (-/-) neonates, neither ectopic beats nor re-entry arrhythmias were observed. Thus the increased automaticity and prolonged action potential of the mutant ventricular myocytes were not sufficiently severe to disrupt the sinus pacing of the heart. The Kir2.1 (-/-) mice, however, had consistently slower heart rates and this phenotype is likely to arise indirectly from the influence of Kir2.1 outside the heart. 5. Thus Kir2.1 is the major component of murine I(K1) and the Kir2.1 (-/-) mouse provides a model in which the functional consequences of removing I(K1) can be studied at both cellular and organismal levels.
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