Sequential gating in the human heart K(+) channel Kv1.5 incorporates Q(1) and Q(2) charge components

On-gating current from the Kv1.5 cardiac delayed rectifier K(+) channel expressed in HEK-293 cells was separated into two distinct charge systems, Q(1) and Q(2), obtained from double Boltzmann fits to the charge-voltage relationship. Q(1) and Q(2) had characteristic voltage dependence and sensitivity with half-activation potentials of -29.6 +/- 1.6 and -2.19 +/- 2.09 mV and effective valences of 1. 87 +/- 0.15 and 5.53 +/- 0.27 e(-), respectively. The contribution to total gating charge was 0.20 +/- 0.04 for Q(1) and 0.80 +/- 0.04 (n = 5) for Q(2). At intermediate depolarizations, heteromorphic gating current waveforms resulted from relatively equal contributions from Q(1) and Q(2), but with widely different kinetics. Prepulses to -20 mV moved only Q(1), simplified on-gating currents, and allowed rapid Q(2) movement. Voltage-dependent on-gating current recovery in the presence of 4-aminopyridine (1 mM) suggested a sequentially coupled movement of the two charge systems during channel activation. This allowed the construction of a linear five-state model of Q(1) and Q(2) gating charge movement, which predicted experimental on-gating currents over a wide potential range. Such models are useful in determining state-dependent mechanisms of open and closed channel block of cardiac K(+) channels.