The consequences of disrupting cardiac inwardly rectifying K+ current (I-K1) as revealed by the targeted deletion of the murine Kir2.1 and Kir2.2 genes

1. Ventricular myocytes demonstrate a steeply inwardly rectifying K+ curren t termed I-K1. We investigated the molecular basis for murine I-K1 by remov ing the genes encoding Kir2.1 and Kir2.2. The physiological consequences of the loss of these genes were studied in newborn animals because mice lacki ng Kir2.1 have a cleft palate and die shortly after birth. 2. Kir2.1(-/-) ventricular myocytes lack detectable I-K1 in whole-cell reco rdings 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. Sustaine d outward K+ currents and Ba2+ currents through L- and T-type channels were not significantly altered by the mutation. A 50 % reduction in I-K1 was ob served in Kir2.2(-/-) mice, raising the possibility that Kir2.2 can also co ntribute 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 pr olonged action potential of the mutant ventricular myocytes were not suffic iently severe to disrupt the sinus pacing of the heart. The Kir2.1(-/-) mic e, however, had consistently slower heart rates and this phenotype is likel y 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(-/-) mo use provides a model in which the functional consequences of removing I-K1 can be studied at both cellular and organismal levels.