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Am J Physiol Heart Circ Physiol 275: H2016-H2024, 1998;
0363-6135/98 $5.00
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Vol. 275, Issue 6, H2016-H2024, December 1998

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

Toshihisa Nagatomo1, Zheng Fan1, Bin Ye1, Gayle S. Tonkovich2, Craig T. January1, John W. Kyle2, and Jonathan C. Makielski1

1 Department of Medicine, University of Wisconsin, Madison, Wisconsin 53792; and 2 Department of Pharmacology and Physiology, University of Chicago, Chicago, Illinois 60637

Na+ current (INa) 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. INa kinetics depend strongly on temperature, but INa for hH1 has been studied previously only at room temperature. We characterized early INa (the peak and initial decay) and late INa 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°C using whole cell patch clamp. Activation and inactivation kinetics for early INa 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 INa (<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 INa at 240 ms was significantly greater for Delta KPQ than for the wild type at both temperatures. The majority of late INa for Delta KPQ was not persistent; rather, it decayed slowly, and this late component exhibited slower recovery from inactivation compared with peak INa. Additional kinetic changes for early and peak INa 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°C and that may underlie the electrophysiological and clinical phenotype of congenital long Q-T Na+ channel syndromes.

long Q-T syndrome; human heart; ion channels; sodium current


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