Abstract

L-type Ca2+ channels (LTCCs) play a crucial role in excitation–contraction coupling and release of hormones from secretory cells. They are targets of antihypertensive and antiarrhythmic drugs such as diltiazem. Here, we present a photoswitchable diltiazem, FHU-779, which can be used to reversibly block endogenous LTCCs by light. FHU-779 is as potent as diltiazem and can be used to place pancreatic β-cell function and cardiac activity under optical control.

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References

  1. 1.

    Zamponi, G. W., Striessnig, J., Koschak, A. & Dolphin, A. C. Pharmacol. Rev. 67, 821–870 (2015).

  2. 2.

    Catterall, W. A., Wisedchaisri, G. & Zheng, N. Nat. Chem. Biol. 13, 455–463 (2017).

  3. 3.

    Wheeler, D. G., Barrett, C. F., Groth, R. D., Safa, P. & Tsien, R. W. J. Cell Biol. 183, 849–863 (2008).

  4. 4.

    Rorsman, P. & Ashcroft, F. M. Physiol. Rev. 98, 117–214 (2018).

  5. 5.

    Kepplinger K.J.F. & Romanin C. in Voltage-Gated Calcium Channels (ed. Zamponi, G.W.) 219–230 (2005).

  6. 6.

    Grissmer, S. et al. Mol. Pharmacol. 45, 1227–1234 (1994).

  7. 7.

    Shabbir, W. et al. Br. J. Pharmacol. 162, 1074–1082 (2011).

  8. 8.

    Grynkiewicz, G., Poenie, M. & Tsien, R. Y. J. Biol. Chem. 260, 3440–3450 (1985).

  9. 9.

    Mori, M. X., Erickson, M. G. & Yue, D. T. Science 304, 432–435 (2004).

  10. 10.

    Freedman, S. B., Dawson, G., Villereal, M. L. & Miller, R. J. J. Neurosci. 4, 1453–1467 (1984).

  11. 11.

    Hockerman, G. H., Dilmac, N., Scheuer, T. & Catterall, W. A. Mol. Pharmacol. 58, 1264–1270 (2000).

  12. 12.

    Zhang, Y. et al. J. Biol. Chem. 291, 20113–20124 (2016).

  13. 13.

    Lenaeus, M. J. et al. Proc. Natl Acad. Sci. USA 114, E3051–E3060 (2017).

  14. 14.

    Tikhonov, D. B. & Zhorov, B. S. J. Biol. Chem. 283, 17594–17604 (2008).

  15. 15.

    Rutter, G. A., Pullen, T. J., Hodson, D. J. & Martinez-Sanchez, A. Biochem. J. 466, 203–218 (2015).

  16. 16.

    Cook, D. L. & Ikeuchi, M. Diabetes 38, 416–421 (1989).

  17. 17.

    Bell, R. M., Mocanu, M. M. & Yellon, D. M. J. Mol. Cell. Cardiol. 50, 940–950 (2011).

  18. 18.

    Lapp, H. et al. Sci. Rep. 7, 9629 (2017).

  19. 19.

    Morad, M., Goldman, Y. E. & Trentham, D. R. Nature 304, 635–638 (1983).

  20. 20.

    Gurney, A. M. & Lester, H. A. Physiol. Rev. 67, 583–617 (1987).

  21. 21.

    Mourot, A. et al. Nat. Methods 9, 396–402 (2012).

  22. 22.

    Li, D. S., Yuan, Y. H., Tu, H. J., Liang, Q. L. & Dai, L. J. Nat. Protoc. 4, 1649–1652 (2009).

  23. 23.

    Bruegmann, T. et al. Nat. Methods 7, 897–900 (2010).

  24. 24.

    Schindelin, J. et al. Nat. Methods 9, 676–682 (2012).

  25. 25.

    Frank, J. A. et al. Chem. Sci. 8, 7604–7610 (2017).

  26. 26.

    Tikhonov, D. B. & Zhorov, B. S. J. Gen. Physiol. 149, 465–481 (2017).

  27. 27.

    Allen, F. H. et al. J. Chem. Soc., Perkin Trans. 2, s1–s19 (1987). 1987.

  28. 28.

    Dewar, M. J. S., Zoebisch, E. G., Healy, E. F. & Stewart, J. J. P. J. Am. Chem. Soc. 107, 3902–3909 (1985).

  29. 29.

    Garden, D. P. & Zhorov, B. S. J. Comput. Aided Mol. Des. 24, 91–105 (2010).

  30. 30.

    Zhorov, B. S. & Tikhonov, D. B. J. Neurochem. 88, 782–799 (2004).

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Acknowledgements

We would like to thank G.R. Lewin and M. Moroni (MDC Berlin) for the TRAAK-GFP construct, M.B. Johnny (Johns Hopkins University) for Cav1.2Δ1671-G12-CaMMUT construct, J. Striessnig (University of Innsbruck) for Cav1.3, Cav1.2, β3, α2δ constructs and H. Abriel (University of Bern) for a HEK293 stable cell line expressing Nav1.5. T.F. and J.G.D thank S.W. Hell for general support. D.T. was supported by the Deutsche Forschungsgemeinschaft (SFB 749) and Center for Integrated Protein Science Munich (CIPSM). M.S. was supported by the DFG (SPP1926). N.K. was supported by the Deutsche Forschungsgemeinschaft (SFB 1116, TP A01) and the BMBF (DZHK, FKZ: 81 × 2800159). D.J.H. was supported by a Diabetes UK R.D. Lawrence (12/0004431) and EFSD/Novo Nordisk Rising Star Fellowships, a Wellcome Trust Institutional Support Award, and COMPARE Primer, MRC Project (MR/N00275X/1) and ERC Starting Grants (OptoBETA; 715884). N.H. thanks the “Deutsche Telekom Stiftung” and the LMUMentoring program for financial support. B.S.Z. acknowledges grants from NSERC, Canada (GRPIN-2014-04894) and Russian Science Foundation (17-15-01292). P.S. was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, GRK1873, SA 1785/7-1, SA 1785/9-1).

Author information

Author notes

    • Florian M. E. Huber

    Present address: Roche Diagnostics GmbH, DXRERA, Penzberg, Germany

    • James A. Frank

    Present address: Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, MA, USA

    • Johann G. Danzl

    Present address: Institute of Science and Technology Austria, Klosterneuburg, Austria

  1. These authors contributed equally: Timm Fehrentz, Florian M.E. Huber.

Affiliations

  1. Institute of Neural and Sensory Physiology, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany

    • Timm Fehrentz
    •  & Nikolaj Klöcker
  2. Department of Chemistry, University of Munich and Center for Integrated Protein Science (CIPSM), Munich, Germany

    • Florian M. E. Huber
    • , Nina Hartrampf
    • , James A. Frank
    • , Martin Sumser
    •  & Dirk Trauner
  3. Institute of Physiology I, Medical Faculty, University of Bonn, Bonn, Germany

    • Tobias Bruegmann
    • , Daniela Malan
    •  & Philipp Sasse
  4. Research Training Group 1873, University of Bonn, Bonn, Germany

    • Tobias Bruegmann
  5. Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK

    • Nicholas H. F. Fine
    •  & David J. Hodson
  6. Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK

    • Nicholas H. F. Fine
    •  & David J. Hodson
  7. Department of NanoBiophotonics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany

    • Johann G. Danzl
  8. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia

    • Denis B. Tikhonov
    •  & Boris S. Zhorov
  9. Institute of Molecular Biology and Genetics, Almazov Federal Heart, Blood and Endocrinology Centre, St. Petersburg, Russia

    • Boris S. Zhorov
  10. Department of Biochemistry & Biomedical Sciences, McMaster University, Hamilton, Canada

    • Boris S. Zhorov
  11. Department of Chemistry and Neuroscience Institute, New York University, New York, NY, USA

    • Dirk Trauner

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Contributions

The project was conceived by T.F., N.K. and D.T. Patch-clamp characterization of FHU-779 was carried out by T.F., J.A.F., D.M., T.B. and J.G.D. Ratiometric Ca2+ imaging in HEK293T cells was performed by T.F. and M.S. Ca2+ imaging of pancreatic islets was carried out by N.H.F.F and D.J.H. Heart-rate modulation on Langendorff-perfused hearts was performed by T.B., T.F. and P.S. and FP experiments by D.M. and P.S. Molecular modeling was performed by D.B.T. and B.S.Z. Synthesis of FHU-779 was carried out by F.M.E.H. and N.H. T.F., D.T. and N.K. wrote the manuscript with contributions from all authors.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Timm Fehrentz or Nikolaj Klöcker or Dirk Trauner.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Tables 1–2, Supplementary Figures 1–10

  2. Reporting Summary

  3. Supplementary Note 1

  4. Supplementary Video 1

    Depolarization of HEK293T cells expressing Cav1.2Δ1671-G12-CaMMUT, β3, α2δ1 and TRAAK-GFP.

  5. Supplementary Video 2

    Photoswitching of Ca2+ influx into HEK293T expressing Cav1.2Δ1671-G12-CaMMUT, β3, α2δ1 and TRAAK-GFP.

  6. Supplementary Video 3

    Optical control of Ca2+ influx into HEK293T cells expressing Cav1.2Δ1671-G12-CaMMUT, β3, α2δ1 and TRAAK-GFP in the presence of 10 mM diltiazem.

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DOI

https://doi.org/10.1038/s41589-018-0090-8

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