A synergistic blocking effect of Mg2+ and spermine on the inward rectifier K+ (Kir2.1) channel pore

Inward rectifier K+ channels (Kir2.1) exhibit an extraordinary rectifying feature in the current-voltage relationship. We have previously showed that the bundle-crossing region of the transmembrane domain constitutes the crucial segment responsible for the polyamine block. In this study, we demonstrated that the major blocking effect of intracellular Mg2+ on Kir2.1 channels is also closely correlated with K+ current flow, and the coupled movements of Mg2+ and K+ seem to happen in the same flux-coupling segment of the pore as polyamines. With a preponderant outward K+ flow, intracellular Mg2+ would also be pushed to and thus stay at the outermost site of a flux-coupling segment in the bundle-crossing region of Kir2.1 channels to block the pore, although with a much lower apparent affinity than spermine (SPM). However, in contrast to the evident possibilities of outward exit of SPM through the channel pore especially during strong membrane depolarization, intracellular Mg2+ does not seem to traverse the Kir2.1 channel pore in any case. Intracellular Mg2+ and SPM therefore may have a synergistic action on the pore-blocking effect, presumably via prohibition of the outward exit of the higher-affinity blocking SPM by the lower-affinity Mg2+