Science Topics – 124

In the cardiac myocytes, the strong inward rectifier K⁺ current (I_K1 in the heart) determines the resting potential and facilitates the rapid repolarization at the final phase of action potentials. Because the open-channel conductance of the strong inward rectifier K⁺ current is apparently proportional to the "square root" of the extracellular K⁺ concentration ([K⁺]_out), increases/decreases in [K⁺]_out induce paradoxical increase/decrease in the outward currents of I_K1 at membrane potentials near the reversal potential, which together with the shift in the voltage dependence of the current with the K⁺ equilibrium potential, affects the repolarization and action-potential duration of cardiac myocytes. In this study, we studied Kir2.1, which is the canonical member of the strong inward rectifier K⁺ channel, under the condition where currents showed little inward rectification by washout of cytoplasmic polyamines. The results showed that the external K⁺ is not required to open this channel and that the noted square-root proportionality of the open channel conductance to [K]_out is mediated by the fast pore blockade by the external Na⁺, which is competitive with the external K⁺. The results reveal that the paradoxical increase/decrease in outward currents of cardiac I_K1 during alternations in [K⁺]_out,　which　accelerates/decelerates　ventricular　repolarization　during hyperkalemia/hypokalemia, is caused by competition from impermeant extracellular Na⁺.

Ishihara K.
External K⁺ dependence of strong inward rectifier K⁺ channel conductance is caused not by K⁺ but by competitive pore blockade by external Na⁺.
Journal of General Physiology. 150(7): 977-989, 2018.

＜Figure Legends＞
External K⁺ concentration ([K⁺]_out) dependence of strong inward rectifier K⁺ current reconstructed using the parameters of the Na⁺ block in competition with external K⁺.
Left, an increase in external K⁺ ions surmount the fast-pore block of the strong inward rectifier K⁺ channel by external Na⁺, thereby increasing both the inward and outward currents. Right, theoretical current (I) – voltage (V) relationships calculated at 3.5 mM (blue), 8 mM (green), and 20 mM (magenta) [K⁺]_out levels.
With no cytoplasmic polyamines, the I – V relationships are almost linear and the conductances show little [K⁺]_out dependence in the absence of external Na⁺ (dotted lines with bold colors). As [K⁺]_out is lowered in the presence of 140 mM external Na⁺, the conductances decrease due to the increase in the Na⁺ block (continuous lines with bold colors). In the I – V relationships showing a strong inward rectification due to the channel blockade by cytoplasmic polyamines, changes in [K⁺]_out also alter the current amplitudes by enhancing/suppressing the Na⁺ block of polyamine-unblocked channels (continuous lines with faint colors).

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