MULTIPLE EFFECTS OF KPQ DELETION MUTATION ON GATING OF HUMAN CARDIAC NA-CELLS( CHANNELS EXPRESSED IN MAMMALIAN)

Several aspects of the effect of the KPQ deletion mutation on Na+ chan nel gating remain unresolved. We have analyzed the kinetics of the ear ly and late currents by recording whole cell and single-channel curren ts in a human embryonic kidney (HEK) cell line (HEK293) expressing wil d-type and KPQ deletion mutation in cardiac Na+ channels. The rate of inactivation increased three-to fivefold between -40 and -80 mV in the mutant channel. The rate of recovery from inactivation was increased twofold. Two modes of gating accounted for the late current: 1) isolat ed brief openings with open times that were weakly voltage dependent a nd the same as the initial transient and 2) bursts of opening with hig hly voltage-dependent prolonged open times. Latency to first opening w as accelerated, suggesting an acceleration of the rate of activation. The Delta KPQ mutation has multiple effects on activation and inactiva tion. The aggregate effects may account for the increased susceptibili ty to arrhythmias.