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Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):E4036-44. doi: 10.1073/pnas.1313247110. Epub 2013 Sep 30.

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

Author information

1
Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena and Jena University Hospital, D-07745 Jena, Germany.

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.

KEYWORDS:

A-type channel; N-type inactivation; NMR; cysteine; intrinsically disordered domain

PMID:
24082096
PMCID:
PMC3801010
DOI:
10.1073/pnas.1313247110
[Indexed for MEDLINE]
Free PMC Article

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