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Haem can bind to and inhibit mammalian calcium-dependent Slo1 BK channels

Nature volume 425, pages 531–535 (2003)Cite this article

Abstract

Haem is essential for living organisms, functioning as a crucial element in the redox-sensitive reaction centre in haemproteins1. During the biogenesis of these proteins, the haem cofactor is typically incorporated enzymatically into the haem pockets of the apo-haemprotein as the functionally indispensable prosthetic group2,3. A class of ion channel, the large-conductance calcium-dependent Slo1 BK channels, possesses a conserved haem-binding sequence motif. Here we present electrophysiological and structural evidence showing that haem directly regulates cloned human Slo1 channels and wild-type BK channels in rat brain. Both oxidized and reduced haem binds to the hSlo1 channel protein and profoundly inhibits transmembrane K+ currents by decreasing the frequency of channel opening. This direct regulation of the BK channel identifies a previously unknown role of haem as an acute signalling molecule.

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Figure 1: Haemin inhibits the opening of Slo1 channels.
Figure 2: Physiological relevance of haem inhibition.
Figure 3: Haemin binding to hSlo-HBP23.
Figure 4: Mutations in the CKACH segment disrupt the haemin sensitivity of the hSlo1 channel.

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Acknowledgements

We thank L. Ciali for critically reading the manuscript; V. Avdonin and R. Wassef for help with constructing the mutants; and P. Angiolillo for use of the EPR spectrometer. This work was supported, in part, by the NIH and the American Heart Association.

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Authors and Affiliations

  1. Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA

    Xiang Dong Tang, Rong Xu & Toshinori Hoshi

  2. Department of Chemistry, Saint Joseph's University, 5600 City Avenue, Philadelphia, Pennsylvania, 19131, USA

    Mark F. Reynolds

  3. Department of Ion Channels, Merck Research Laboratories, PO Box 2000, Rahway, New Jersey, 07065, USA

    Maria L. Garcia

  4. Research Unit Molecular and Cellular Biophysics, Medical Faculty of the Friedrich Schiller University Jena, Drackendorfer Strasse 1, D-07747, Jena, Germany

    Stefan H. Heinemann

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  1. Xiang Dong Tang
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Correspondence to Toshinori Hoshi.

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M. L. Garcia is an employee of Merck & Co. Inc. and potentially owns stock and/or holds stock options in the company.

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Tang, X., Xu, R., Reynolds, M. et al. Haem can bind to and inhibit mammalian calcium-dependent Slo1 BK channels. Nature 425, 531–535 (2003). https://doi.org/10.1038/nature02003

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