Multiple effects of KPQ deletion mutation on gating of human cardiac Na1 channels expressed in mammalian cells

Chandra, Rashmi, C. Frank Starmer, and Augustus O. Grant. Multiple effects of KPQ deletion mutation on gating of human cardiac Na1 channels expressed in mammalian cells. Am. J. Physiol. 274 (Heart Circ. Physiol. 43): H1643–H1654, 1998.—Several aspects of the effect of the KPQ deletion mutation on Na1 channel gating remain unresolved. We have analyzed the kinetics of the early and late currents by recording whole cell and single-channel currents in a human embryonic kidney (HEK) cell line (HEK293) expressing wild-type and KPQ deletion mutation in cardiac Na1 channels. The rate of inactivation increased threeto fivefold between 240 and 280 mV in the mutant channel. The rate of recovery from inactivation was increased twofold. Two modes of gating accounted for the late current: 1) isolated brief openings with open times that were weakly voltage dependent and the same as the initial transient and 2) bursts of opening with highly voltage-dependent prolonged open times. Latency to first opening was accelerated, suggesting an acceleration of the rate of activation. The DKPQ mutation has multiple effects on activation and inactivation. The aggregate effects may account for the increased susceptibility to arrhythmias.