Kinetic analysis of the effects of H+ or Ni2+on Kv1.5 current shows that both ions enhance slow inactivation and induce resting inactivation

External H+ and Ni2+ ions inhibit Kv1.5 channels by increasing current decay during a depolarizing pulse and reducing the maximal conductance. Although the former may be attributed to an enhancement of slow inactivation occurring from the open state, the latter cannot. Instead, we propose that the loss of conductance is due to the induction, by H+ or Ni2+, of a resting inactivation process. To assess whether the two inactivation processes are mechanistically related, we examined the time courses for the onset of and recovery from H+- or Ni2+-enhanced slow inactivation and resting inactivation. Compared to the time course of H+- or Ni2+-enhanced slow inactivation at +50 mV, the onset of resting inactivation induced at -80 mV with either ion involves a relatively slower process. Recovery from slow inactivation under control conditions was bi-exponential, indicative of at least two inactivated states. Recovery following H+- or Ni2+-enhanced slow inactivation or resting inactivation had time constants similar to those for recovery from control slow inactivation, although H+ and Ni2+ biased inactivation towards states from which recovery was fast and slow, respectively. The shared time constants suggest that the H+- and Ni2+-enhanced slow inactivated and induced resting inactivated states are similar to those visited during control slow inactivation at pH 7.4. We conclude that in Kv1.5 H+ and Ni2+ differentially enhance a slow inactivation process that involves at least two inactivated states and that resting inactivation is probably a close variant of slow inactivation.