Haem can bind to and inhibit mammalian calcium-dependent Slo1 BK channels (original) (raw)

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.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 51 print issues and online access

$199.00 per year

only $3.90 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

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)
    Article ADS CAS Google Scholar
  3. Ponka, P. Cell biology of heme. Am. J. Med. Sci. 318, 241–256 (1999)
    Article ADS CAS 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)
    Article ADS CAS 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)
    Article CAS 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)
    Article CAS 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)
    Article CAS 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)
    Article CAS 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)
    Article ADS CAS 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)
    Article CAS 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)
    Article CAS 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)
    Article ADS CAS 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)
    Article CAS 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)
    Article CAS Google Scholar
  19. Tang, X. D. et al. Oxidative regulation of large conductance calcium-activated potassium channels. J. Gen. Physiol. 117, 253–274 (2001)
    Article CAS Google Scholar

Download references

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.

Author information

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

Authors

  1. Xiang Dong Tang
    You can also search for this author inPubMed Google Scholar
  2. Rong Xu
    You can also search for this author inPubMed Google Scholar
  3. Mark F. Reynolds
    You can also search for this author inPubMed Google Scholar
  4. Maria L. Garcia
    You can also search for this author inPubMed Google Scholar
  5. Stefan H. Heinemann
    You can also search for this author inPubMed Google Scholar
  6. Toshinori Hoshi
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toToshinori Hoshi.

Ethics declarations

Competing interests

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

Supplementary information

Rights and permissions

About this article

Cite this article

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

Download citation

This article is cited by