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Carta, Valentina; Pangerl, Michael; Baur, Roland; Puthenkalam, Roshan; Ernst, Margot; Trauner, Dirk and Sigel, Erwin (2014): A Pentasymmetric Open Channel Blocker for Cys-Loop Receptor Channels.
In: PLOS ONE 9(9), e106688 [PDF, 1MB]

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gamma-Aminobutyric acid type A receptors (GABA(A) receptors) are chloride ion channels composed of five subunits, mediating fast synaptic and tonic inhibition in the mammalian brain. These receptors show near five-fold symmetry that is most pronounced in the second trans-membrane domain M2 lining the Cl- ion channel. To take advantage of this inherent symmetry, we screened a variety of aromatic anions with matched symmetry and found an inhibitor, pentacyanocyclopentdienyl anion (PCCP-) that exhibited all characteristics of an open channel blocker. Inhibition was strongly dependent on the membrane potential. Through mutagenesis and covalent modification, we identified the region alpha(1)V256-alpha(1)T261 in the rat recombinant GABA(A) receptor to be important for PCCP- action. Introduction of positive charges into M2 increased the affinity for PCCP- while PCCP- prevented the access of a positively charged molecule into M2. Interestingly, other anion selective cys-loop receptors were also inhibited by PCCP-, among them the Drosophila RDL GABA(A) receptor carrying an insecticide resistance mutation, suggesting that PCCP- could serve as an insecticide.

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