Abstract 16741: Critical Roles for Trek1- and Task1- Encoded Two-Pore Domain K+ Currents in the Regulation of Ventricular Repolarization
Background: Previous studies have demonstrated expression of the two-pore domain K+ (K2P) channel subunits, TREK1 and TASK1, in mammalian ventricles. Although channels encoded by these subunits are regulated by a variety of physiological and pathological stimuli, the functional roles of TREK1 and TASK1 in the generation of native cardiac K+ currents are poorly understood.
Methods and Results: Electrophysiological experiments were completed on TREK1 (TREK1-/-) and TASK1 (TASK1-/-) deficient mice to explore the functional roles of these K2P channel subunits directly. Surface ECG recordings revealed marked (P<0.001) rate corrected QT prolongation in TREK1-/- (54±1.7 ms) and TASK1-/- (55±4.2 ms), compared with wild type (WT) (45±1.1 ms), mice. In addition, action potential durations recorded from left ventricular (LV) myocytes were significantly prolonged in TREK1-/- (P<0.05) and in TASK1-/- (P<0.05), compared with WT, cells. Importantly, resting membrane potentials were depolarized to -73±0.7 mV (P<0.001) in TREK1-/- and to -75±1 mV (P<0.05) in TASK1-/- LV cells, compared with (-77±0.4 mV) WT LV cells. The densities of the voltage-gated outward K+ currents, Ito,f and IK,slow, were similar in TREK1-/-, TASK1-/- and WT cells, whereas steady-state outward K+ current (Iss) densities were significantly (P<0.001) lower in TREK1-/- and TASK1-/-, than in WT, LV cells. Additional experiments revealed that Iss in WT and TASK1-/- cells was reversibly increased >2 fold (P<0.01) by 30 µM arachidonic acid; the arachidonic acid sensitive component of Iss was abolished in TREK1-/- myocytes. In addition, Iss in WT cells was sensitive to changes in extracellular pH: Iss density was reversibly decreased by 30% (P<0.01) at pH6.4 and reversibly increased by 50% (P<0.05) at pH8.4. The extracellular pH sensitive component of Iss was eliminated in TASK1-/- myocytes.
Conclusion: These results reveal roles for TREK1- and TASK1-encoded, K+ channels in the generation of Iss in mouse ventricular myocytes, in determining ventricular resting membrane potentials and in regulating action potential repolarization. In addition, these distinct current components are differentially and reversibly affected by changes in extracellular fatty acids (TREK1) and pH (TASK1).
- © 2012 by American Heart Association, Inc.