Optical control of L-type Ca2+ channels using a diltiazem photoswitch

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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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Fig. 1: Design and characterization of the light-regulated diltiazem derivative FHU-779.
Fig. 2: FHU-779 allows photoswitching of LTCC in pancreatic β cells, cardiomyocytes and mouse hearts.

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  • 02 August 2019

    In the version of this article originally published, numbered compounds were not linked correctly to their respective compound pages. The error has been corrected in the HTML version of this paper.

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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).

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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.

Corresponding authors

Correspondence to Timm Fehrentz or Nikolaj Klöcker or Dirk Trauner.

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The authors declare no competing interests.

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Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–2, Supplementary Figures 1–10

Reporting Summary

Supplementary Note 1

Supplementary Video 1

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

Supplementary Video 2

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

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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Fehrentz, T., Huber, F.M.E., Hartrampf, N. et al. Optical control of L-type Ca2+ channels using a diltiazem photoswitch. Nat Chem Biol 14, 764–767 (2018). https://doi.org/10.1038/s41589-018-0090-8

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