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J Gen Physiol. 2018 Jul 2;150(7):977-989. doi: 10.1085/jgp.201711936. Epub 2018 Jun 15.

External K+ dependence of strong inward rectifier K+ channel conductance is caused not by K+ but by competitive pore blockade by external Na.

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Department of Physiology, Kurume University School of Medicine, Kurume, Japan


Strong inward rectifier K+ (sKir) channels determine the membrane potentials of many types of excitable and nonexcitable cells, most notably the resting potentials of cardiac myocytes. They show little outward current during membrane depolarization (i.e., strong inward rectification) because of the channel blockade by cytoplasmic polyamines, which depends on the deviation of the membrane potential from the K+ equilibrium potential (V - EK) when the extracellular K+ concentration ([K+]out) is changed. Because their open-channel conductance is apparently proportional to the "square root" of [K+]out, increases/decreases in [K+]out enhance/diminish outward currents through sKir channels at membrane potentials near their reversal potential, which also affects, for example, the repolarization and action-potential duration of cardiac myocytes. Despite its importance, however, the mechanism underlying the [K+]out dependence of the open sKir channel conductance has remained elusive. By studying Kir2.1, the canonical member of the sKir channel family, we first show that the outward currents of Kir2.1 are observed under the external K+-free condition when its inward rectification is reduced and that the complete inhibition of the currents at 0 [K+]out results solely from pore blockade caused by the polyamines. Moreover, the noted square-root proportionality of the open sKir channel conductance to [K+]out is mediated by the pore blockade by the external Na+, which is competitive with the external K+ Our results show that external K+ itself does not activate or facilitate K+ permeation through the open sKir channel to mediate the apparent external K+ dependence of its open channel conductance. The paradoxical increase/decrease in outward sKir channel currents during alternations in [K+]out, which is physiologically relevant, is caused by competition from impermeant extracellular Na.

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