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

Nadine J. Ortner, Gabriella Bock, David H.F. Vandael, Robert Mauersberger, Henning J. Draheim, Ronald Gust, Emilio Carbone, Petronel Tuluc and Jörg Striessnig ()
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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

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4897

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