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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

Joshua J. Zaritsky, John B. Redell *, Bruce L Tempel * and Thomas L. Schwarz

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 Ba²⁺ 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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