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The inward rectification of the inward rectifier K+ channels has been reported to be caused by both the block of the outward current by cytoplasmic Mg2+ and by intrinsic channel gating. Recently it was uncovered that the apparent intrinsic gating is mostly due to a block by cytoplasmic polyamines which is actually extrinsic to the channel. Furthermore, negatively charged amino-acid residues in the center of the M2 region and in the C-terminal hydrophilic domain were identified to be involved in the binding of these blockers to the channels. The inward rectifier shows consistent inward rectification at various extracellular K+ concentrations ([K+]o). To explain the dependency of the channel activity on Ko+, the hypothesis that Ko+ interacts with the inward rectifier K+ channel and thereby activates it (K(+)-activated K+ channel model) has been postulated. In this manuscript, the history and recent progresses of the study of the inward rectification mechanism, especially the effect of the cytoplasmic blockers and Ko+, is reviewed.

Two Aspects of the Inward Rectification Mechanism. Effects of Cytoplasmic Blockers ant Extracellular K+ on the Inward Rectifier K+ Channel.