Effects of permeant cations on K+ channel gating in nerve axons revisited

An increase in extracellular potassium ion concentration, Ko, significantly slows the potassium channel deactivation rate in squid giant axons, as previously shown. Surprisingly, the effect does not occur in all preparations which, coupled with the voltage independence of this result in preparations in which it does occur, suggests that it is mediated at a site outside of the electric field of the channel, and that this site is accessible to potassium ions in some preparations, but not in others. In other words, the effect does not appear to be related to occupancy of the channel by potassium ions. This conclusion is supported by a four-barrier, three-binding site model of single file diffusion through the channel in which one site, at most, is unoccupied by a potassium ion (single-vacancy model). The model is consistent with current-voltage relations with various levels of Ko, and, by definition, with multiple occupancy by K+. The model predicts that occupancy of any given site is essentially independent of Ko (or Ki). The effects of extracellular Rb+ and Cs+ on gating are strongly voltage dependent, and they were observed in all preparations investigated. Consequently, the mechanism underlying these results would appear to be different from that which underlies the effect of K+ on gating. In particular, the effect of Rb+ on gating is reduced by strong hyperpolarization, which in the context of the occupancy hypothesis, is consistent with the voltage dependence of the current-voltage relation in the presence of Rb+. The primary, novel, finding in this study is that the effects of Cs+ are counterintuitive in this regard. Specifically, the slowing of channel deactivation rate by Cs+ is also reduced by hyperpolarization, similar to the Rb+ results, whereas blockade is enhanced, which is seemingly inconsistent with the concept that occupancy of the channel by Cs+ underlies the effect of this ion on gating. This result is further elucidated by barrier modeling of the current-voltage relation in the presence of Cs+.