Heme impairs the ball-and-chain inactivation of potassium channels

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Abstract

Fine-tuned regulation of K+ channel inactivation enables excitable cells to adjust action potential firing. Fast inactivation present in some K+ channels is mediated by the distal N-terminal structure (ball) occluding the ion permeation pathway. Here we show that Kv1.4 K + channels are potently regulated by intracellular free heme; heme binds to the N-terminal inactivation domain and thereby impairs the inactivation process, thus enhancing the K+ current with an apparent EC 50 value of ~20 nM. Functional studies on channel mutants and structural investigations on recombinant inactivation ball domain peptides encompassing the first 61 residues of Kv1.4 revealed a heme-responsive binding motif involving Cys13:His16 and a secondary histidine at position 35. Heme binding to the N-terminal inactivation domain induces a conformational constraint that prevents it from reaching its receptor site at the vestibule of the channel pore.

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Sahoo, N., Goradia, N., Ohlenschläger, O., Schönherr, R., Friedrich, M., Plass, W., … Heinemann, S. H. (2013). Heme impairs the ball-and-chain inactivation of potassium channels. Proceedings of the National Academy of Sciences of the United States of America, 110(42). https://doi.org/10.1073/pnas.1313247110

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