The consequences of disrupting cardiac inwardly rectifying K+ current (IK1) as revealed by the targeted deletion of the murine Kir2.1 and Kir2.2 genes
JJ Zaritsky, JB Redell, BL Tempel… - The Journal of …, 2001 - Wiley Online Library
JJ Zaritsky, JB Redell, BL Tempel, TL Schwarz
The Journal of physiology, 2001•Wiley Online Library1 Ventricular myocytes demonstrate a steeply inwardly rectifying K+ current termed IK1. We
investigated the molecular basis for murine IK1 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 IK1 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 …
investigated the molecular basis for murine IK1 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 IK1 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 …
- 1Ventricular myocytes demonstrate a steeply inwardly rectifying K+ current termed IK1. We investigated the molecular basis for murine IK1 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.
- 2Kir2.1 ‐/‐ ventricular myocytes lack detectable IK1 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 IK1. Sustained outward K+ currents and Ba2+ currents through L‐ and T‐type channels were not significantly altered by the mutation. A 50 % reduction in IK1 was observed in Kir2.2‐/‐ mice, raising the possibility that Kir2.2 can also contribute to the native IK1.
- 3Kir2.1 ‐/‐ myocytes showed significantly broader action potentials and more frequent spontaneous action potentials than wild‐type myocytes.
- 4In 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.
- 5Thus Kir2.1 is the major component of murine IK1 and the Kir2.1‐/‐ mouse provides a model in which the functional consequences of removing IK1 can be studied at both cellular and organismal levels.
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