Temperature dependence of early and late currents in human cardiac wild-type and long Q-T ΔKPQ Na+ channels

Na+ current (I-Na) through wild-type human heart Na+ channels (hH1) is important for normal cardiac excitability and conduction, and it participates in the control of repolarization and refractoriness. I-Na kinetics depend strongly on temperature, but I-Na for hH1 has been studied previously only at room temperature. We characterized early I-Na (the peak and initial decay) and late I-Na of the wild-type hH1 channel and a mutant channel (Delta KPQ) associated with congenital long Q-T syndrome. Channels were stably transfected in HEK-293 cells and studied at 23 and 33 degrees C using whole cell patch clamp. Activation and inactivation kinetics for early I-Na were twofold faster at higher temperature for both channels and shifted activation and steady-state inactivation in the positive direction, especially for Delta KPQ. For early I-Na (<24 ms), Delta KPQ decayed faster than the wild type for voltages negative to -20 mV but slower for more positive voltages, suggesting a reduced voltage dependence of fast inactivation. Late I-Na at 240 ms was significantly greater for Delta KPQ than for the wild type at both temperatures. The majority of late I-Na for Delta KPQ was not persistent; rather, it decayed slowly, and this late component exhibited slower recovery from inactivation compared with peak I-Na Additional kinetic changes for early and peak I-Na for Delta KPQ compared with the wild type at both temperatures were 1) reduced voltage dependence of steady-state inactivation with no difference in midpoint, 2) positive shift for activation kinetics, and 3) more rapid recovery from inactivation. This study represents the first description of human Na+ channel kinetics near physiological temperature and also demonstrates complex gating changes in the Delta KPQ that are present at 33 degrees C and that may underlie the electrophysiological and clinical phenotype of congenital long Q-T Na+ channel syndromes.