Gating current studies reveal both intra- and extracellular cation modulation of K+ channel deactivation

1. The presence of permeant ions can modulate the rate of gating charge ret urn in wild-type human heart K+ (hKv1.5) channels. Here we employ gating cu rrent measurements in a non-conducting mutant, W472F, of the hKv1.5 channel to investigate how different cations can modulate charge return and whethe r the actions can be specifically localized at the internal as well as the external mouth of the channel pore. 2. Intracellular cations were effective at accelerating charge return in th e sequence Cs+ > Rb+ > K+ > Na+ > NMG(+). Extracellular cations accelerated charge return with the selectivity sequence Cs+ > Rb+ > Na+ = NMG(+). 3. Intracellular and extracellular cation actions were of relatively low af finity. The K-d for preventing slowing of the time constant of the off-gati ng current decay (tau(off)) was 20.2 mM for intracellular Cs+ (Cs-i(+)) and 358 mM for extracellular Cs+ (Cs-o(+)). 4. Both intracellular and extracellular cations can regulate the rate of ch arge return during deactivation of hKv1.5, but intracellular cations are mo re effective. We suggest that ion crystal radius is an important determinan t of this action, with larger ions preventing slowing more effectively. Imp ortant parallels exist with cation-dependent modulation of slow inactivatio n of ionic currents in this channel. However, further experiments are requi red to understand the exact relationship between acceleration of charge ret urn and the slowing of inactivation of ionic currents by cations.