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

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.

References

  1. Granick, S. & Beale, S. I. Hemes, chlorophylls, and related compounds: biosynthesis and metabolic regulation. Adv. Enzymol. Relat. Areas Mol. Biol. 46, 33–203 (1978)

    CAS  PubMed  Google Scholar 

  2. Daltrop, O., Allen, J. W., Willis, A. C. & Ferguson, S. J. In vitro formation of a c-type cytochrome. Proc. Natl Acad. Sci. USA 99, 7872–7876 (2002)

    ADS  CAS  Article  Google Scholar 

  3. Ponka, P. Cell biology of heme. Am. J. Med. Sci. 318, 241–256 (1999)

    ADS  CAS  Article  Google Scholar 

  4. Blackmon, B. J., Dailey, T. A., Lianchun, X. & Dailey, H. A. Characterization of a human and mouse tetrapyrrole-binding protein. Arch. Biochem. Biophys. 407, 196–201 (2002)

    Article  Google Scholar 

  5. Hirotsu, S. et al. Crystal structure of a multifunctional 2-Cys peroxiredoxin heme-binding protein 23 kDa/proliferation-associated gene product. Proc. Natl Acad. Sci. USA 96, 12333–12338 (1999)

    ADS  CAS  Article  Google Scholar 

  6. Taketani, S. et al. Molecular characterization of a newly identified heme-binding protein induced during differentiation of urine erythroleukemia cells. J. Biol. Chem. 273, 31388–31394 (1998)

    CAS  Article  Google Scholar 

  7. Ricci, A. J., Gray-Keller, M. & Fettiplace, R. Tonotopic variations of calcium signalling in turtle auditory hair cells. J. Physiol. (Lond.) 524, 423–436 (2000)

    CAS  Article  Google Scholar 

  8. ZhuGe, R. et al. Dynamics of signaling between Ca2+ sparks and Ca2+-activated K+ channels studied with a novel image-based method for direct intracellular measurement of ryanodine receptor Ca2+ current. J. Gen. Physiol. 116, 845–864 (2000)

    CAS  Article  Google Scholar 

  9. Gribkoff, V. K. et al. Targeting acute ischemic stroke with a calcium-sensitive opener of maxi-K potassium channels. Nature Med. 7, 471–477 (2001)

    CAS  Article  Google Scholar 

  10. Xu, W. et al. Cytoprotective role of Ca2+-activated K+ channels in the cardiac inner mitochondrial membrane. Science 298, 1029–1033 (2002)

    ADS  CAS  Article  Google Scholar 

  11. Dore, S. Decreased activity of the antioxidant heme oxygenase enzyme: implications in ischemia and in Alzheimer's disease. Free Radic. Biol. Med. 32, 1276–1282 (2002)

    CAS  Article  Google Scholar 

  12. More, C. et al. EPR spectroscopy: a powerful technique for the structural and functional investigation of metalloproteins. Biospectroscopy 5, S3–S18 (1999)

    CAS  Article  Google Scholar 

  13. Brautigan, D. L. et al. Multiple low spin forms of the cytochrome c ferrihemochrome. EPR spectra of various eukaryotic and prokaryotic cytochromes c. J. Biol. Chem. 252, 574–582 (1977)

    CAS  PubMed  Google Scholar 

  14. Jiang, Y. et al. Crystal structure and mechanism of a calcium-gated potassium channel. Nature 417, 515–522 (2002)

    ADS  CAS  Article  Google Scholar 

  15. Worthington, M. T., Cohn, S. M., Miller, S. K., Luo, R. Q. & Berg, C. L. Characterization of a human plasma membrane heme transporter in intestinal and hepatocyte cell lines. Am. J. Physiol. 280, G1172–G1177 (2001)

    CAS  Google Scholar 

  16. Siemen, D., Loupatatzis, C., Borecky, J., Gulbins, E. & Lang, F. Ca2+-activated K channel of the BK-type in the inner mitochondrial membrane of a human glioma cell line. Biochem. Biophys. Res. Commun. 257, 549–554 (1999)

    CAS  Article  Google Scholar 

  17. Yermolaieva, O., Tang, X. D., Daggett, H. & Hoshi, T. Calcium-activated mitochondrial K+ channel is involved in regulation of mitochondrial membrane potential and permeability transition. Biophys. J. 80, 950A (2001)

    Google Scholar 

  18. Shaklai, N., Shviro, Y., Rabizadeh, E. & Kirschner-Zilber, I. Accumulation and drainage of hemin in the red cell membrane. Biochim. Biophys. Acta 821, 355–366 (1985)

    CAS  Article  Google Scholar 

  19. Tang, X. D. et al. Oxidative regulation of large conductance calcium-activated potassium channels. J. Gen. Physiol. 117, 253–274 (2001)

    CAS  Article  Google Scholar 

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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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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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