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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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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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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DOI: https://doi.org/10.1038/nature02003
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