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

Nat Commun. 2014 Jun 19:5:3897. doi: 10.1038/ncomms4897.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Barbiturates / chemistry
  • Barbiturates / metabolism*
  • Calcium Channel Agonists / chemistry
  • Calcium Channel Agonists / metabolism*
  • Calcium Channels, L-Type / chemistry
  • Calcium Channels, L-Type / genetics
  • Calcium Channels, L-Type / metabolism*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout

Substances

  • 1-(3-chlorophenethyl)-3-cyclopentylpyrimidine-2,4,6-(1H,3H,5H)-trione
  • Barbiturates
  • CACNA1C protein, mouse
  • CACNA1D protein, human
  • Cacna1d protein, mouse
  • Calcium Channel Agonists
  • Calcium Channels, L-Type
  • L-type calcium channel alpha(1C)