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Reactive oxygen species impair Slo1 BK channel function by altering cysteine-mediated calcium sensing

Nature Structural & Molecular Biology volume 11, pages 171–178 (2004)Cite this article

Abstract

Vascular dysfunction is a hallmark of many diseases, including coronary heart disease, stroke and diabetes. The underlying mechanisms of these disorders, which are intimately associated with inflammation and oxidative stress caused by excess reactive oxygen species (ROS), have remained elusive. Here we report that ROS are powerful inhibitors of vascular smooth muscle calcium-dependent Slo1 BK or Maxi-K potassium channels, an important physiological determinant of vascular tone. By targeting a cysteine residue near the Ca2+ bowl of the BK α subunit, H2O2 virtually eliminates physiological activation of the channel, with an inhibitory potency comparable to a knockout of the auxiliary subunit BK β1. These results reveal a molecular structural basis for the vascular dysfunction involving oxidative stress and provide a solid rationale for a potential use of BK openers in the prevention and treatment of cardiovascular disorders.

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Figure 1: Inhibition of BK currents by H2O2 and MTSEA at physiological [Ca2+]i.
Figure 2: Cys911 mediates the oxidation sensitivity.
Figure 3: MTSEA disrupts Ca2+-dependent activation.
Figure 4: MTSEA selectively disrupts Ca2+ bowl function.
Figure 5: Probable molecular structure of the hSlo channel near Cys911.
Figure 6: Functional knockout of BK channels by ROS.

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Acknowledgements

We thank L. Ciali Santarelli for reading of the manuscript, C. Schinstock and M. Hoshi for help with mutant construction, and R. Xu and H. Daggett for cell culture. X.D.T. dedicates this paper to his grandmother who passed away in June 2003. This work was supported in part by the US National Institutes of Health.

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Authors and Affiliations

  1. Department of Physiology, University of Pennsylvania, 3700 Hamilton Walk, Philadelphia, 19104, Pennsylvania, USA

    Xiang Dong Tang & Toshinori Hoshi

  2. Department of Ion Channels, Merck Research Laboratories, P.O. Box 2000, Rahway, 07065, New Jersey, USA

    Maria L Garcia

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

    Stefan H Heinemann

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Correspondence to Toshinori Hoshi.

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M.L.G. 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., Garcia, M., Heinemann, S. et al. Reactive oxygen species impair Slo1 BK channel function by altering cysteine-mediated calcium sensing. Nat Struct Mol Biol 11, 171–178 (2004). https://doi.org/10.1038/nsmb725

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