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


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 EC50 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.

SUBMITTER: Sahoo N 

PROVIDER: S-EPMC3801010 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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

Sahoo Nirakar N   Goradia Nishit N   Ohlenschläger Oliver O   Schönherr Roland R   Friedrich Manfred M   Plass Winfried W   Kappl Reinhard R   Hoshi Toshinori T   Heinemann Stefan H SH  

Proceedings of the National Academy of Sciences of the United States of America 20130930 42


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 EC50 value of ∼20  ...[more]

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