A pentasymmetric open channel blocker for cys-loop receptor channels

Valentina Carta, Michael Pangerl, Roland Baur, Roshan Puthenkalam, Margot Ernst, Dirk Trauner, Erwin Sigel

Research output: Contribution to journalArticle

Abstract

γ-Aminobutyric acid type A receptors (GABAAreceptors) 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, pentacyanocyclo-pentdienyl 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 α1V256-α1T261 in the rat recombinant GABAAreceptor 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 GABAAreceptor carrying an insecticide resistance mutation, suggesting that PCCP-could serve as an insecticide.

Original languageEnglish (US)
Article numbere106691
JournalPloS one
Volume9
Issue number9
DOIs
StatePublished - Sep 3 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Carta, V., Pangerl, M., Baur, R., Puthenkalam, R., Ernst, M., Trauner, D., & Sigel, E. (2014). A pentasymmetric open channel blocker for cys-loop receptor channels. PloS one, 9(9), [e106691]. https://doi.org/10.1371/journal.pone.0106688