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Pyrimidine-2,4,6-triones are a new class of voltage-gated L-type Ca2+ channel activators

Author

Listed:
  • Nadine J. Ortner

    (Center for Molecular Biosciences, University of Innsbruck)

  • Gabriella Bock

    (Center for Molecular Biosciences, University of Innsbruck)

  • David H.F. Vandael

    (Laboratory of Cellular and Molecular Neuroscience, Nanostructured Interfaces and Surfaces Center)

  • Robert Mauersberger

    (Center for Molecular Biosciences, University of Innsbruck)

  • Henning J. Draheim

    (Boehringer Ingelheim Pharma GmbH & Co KG, CNS Research)

  • Ronald Gust

    (Center for Molecular Biosciences, University of Innsbruck)

  • Emilio Carbone

    (Laboratory of Cellular and Molecular Neuroscience, Nanostructured Interfaces and Surfaces Center)

  • Petronel Tuluc

    (Center for Molecular Biosciences, University of Innsbruck)

  • Jörg Striessnig

    (Center for Molecular Biosciences, University of Innsbruck)

Abstract

Cav1.2 and Cav1.3 are the main L-type Ca2+ channel subtypes in the brain. Cav1.3 channels have recently been implicated in the pathogenesis of Parkinson’s disease. Therefore, Cav1.3-selective blockers are developed as promising neuroprotective drugs. We studied the pharmacological properties of a pyrimidine-2,4,6-trione derivative (1-(3-chlorophenethyl)-3-cyclopentylpyrimidine-2,4,6-(1H,3H,5H)-trione, Cp8) recently reported as the first highly selective Cav1.3 blocker. Here we show, in contrast to this previous study, that Cp8 reproducibly increases inward Ca2+ currents of Cav1.3 and Cav1.2 channels expressed in tsA-201 cells by slowing activation, inactivation and enhancement of tail currents. Similar effects are also observed for native Cav1.3 and Cav1.2 channels in mouse chromaffin cells, while non-L-type currents are unaffected. Evidence for a weak and non-selective inhibition of Cav1.3 and Cav1.2 currents is only observed in a minority of cells using Ba2+ as charge carrier. Therefore, our data identify pyrimidine-2,4,6-triones as Ca2+ channel activators.

Suggested Citation

  • Nadine J. Ortner & Gabriella Bock & David H.F. Vandael & Robert Mauersberger & Henning J. Draheim & Ronald Gust & Emilio Carbone & Petronel Tuluc & Jörg Striessnig, 2014. "Pyrimidine-2,4,6-triones are a new class of voltage-gated L-type Ca2+ channel activators," Nature Communications, Nature, vol. 5(1), pages 1-10, September.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4897
    DOI: 10.1038/ncomms4897
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    Cited by:

    1. Pietro Mesirca & Jean Chemin & Christian Barrère & Eleonora Torre & Laura Gallot & Arnaud Monteil & Isabelle Bidaud & Sylvie Diochot & Michel Lazdunski & Tuck Wah Soong & Stéphanie Barrère-Lemaire & M, 2024. "Selective blockade of Cav1.2 (α1C) versus Cav1.3 (α1D) L-type calcium channels by the black mamba toxin calciseptine," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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