title: Pyrimidine-2,4,6-triones are a new class of voltage-gated L-type Ca2+ channel activators.
abstract: Cav1.2 and Cav1.3 are the main L-type Ca(2+) 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 Ca(2+) 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 Ba(2+) as charge carrier. Therefore, our data identify pyrimidine-2,4,6-triones as Ca(2+) channel activators.
authors.affiliation: 1] Department of Pharmacology and Toxicology, Center for Molecular Biosciences, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria [2].
authors.forename: Nadine J
authors.initials: NJ
authors.lastname: Ortner
authors.affiliation: 1] Department of Pharmacology and Toxicology, Center for Molecular Biosciences, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria [2].
authors.forename: Gabriella
authors.initials: G
authors.lastname: Bock
authors.affiliation: Department of Drug Science, Laboratory of Cellular and Molecular Neuroscience, Nanostructured Interfaces and Surfaces Center, 10125 Torino, Italy.
authors.forename: David H F
authors.initials: DH
authors.lastname: Vandael
authors.affiliation: Department of Pharmaceutical Chemistry, Center for Molecular Biosciences, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Mauersberger
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co KG, CNS Research, Birkendorfer Strasse 65, 88397 Biberach, Germany.
authors.forename: Henning J
authors.initials: HJ
authors.lastname: Draheim
authors.affiliation: Department of Pharmaceutical Chemistry, Center for Molecular Biosciences, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Ronald
authors.initials: R
authors.lastname: Gust
authors.affiliation: Department of Drug Science, Laboratory of Cellular and Molecular Neuroscience, Nanostructured Interfaces and Surfaces Center, 10125 Torino, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Carbone
authors.affiliation: Department of Pharmacology and Toxicology, Center for Molecular Biosciences, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Petronel
authors.initials: P
authors.lastname: Tuluc
authors.affiliation: Department of Pharmacology and Toxicology, Center for Molecular Biosciences, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Jörg
authors.initials: J
authors.lastname: Striessnig
mesh_terms: D000818:Animals; D001463:Barbiturates / Q000737:chemistry / Q000378:metabolism*; D002120:Calcium Channel Agonists / Q000737:chemistry / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: C581561:1-(3-chlorophenethyl)-3-cyclopentylpyrimidine-2,4,6-(1H,3H,5H)-trione; D001463:Barbiturates; C514350:CACNA1C protein, mouse; C472073:CACNA1D protein, human; C485995:Cacna1d protein, mouse; D002120:Calcium Channel Agonists; D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C)