A pentasymmetric open channel blocker for Cys-loop receptor channels.

Carta V; Pangerl M; Baur R; Puthenkalam R; Ernst M; Trauner D; Sigel E

doi:10.1371/journal.pone.0106688

Back

Journal article

A pentasymmetric open channel blocker for Cys-loop receptor channels.

Carta V Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland.
Pangerl M Department of Chemistry, Ludwig-Maximilians-Universität München and Center of Integrated Protein Science, Munich, Germany.
Baur R Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland.
Puthenkalam R Department of Biochemistry and Molecular Biology, Center for Brain Research, Medical University of Vienna, Vienna, Austria.
Ernst M Department of Biochemistry and Molecular Biology, Center for Brain Research, Medical University of Vienna, Vienna, Austria.
Trauner D Department of Chemistry, Ludwig-Maximilians-Universität München and Center of Integrated Protein Science, Munich, Germany.
Sigel E Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland.

2014-09-04

Published in:

PloS one. - 2014

English γ-Aminobutyric acid type A receptors (GABAA 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 α1V256-α1T261 in the rat recombinant GABAA 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 GABAA receptor carrying an insecticide resistance mutation, suggesting that PCCP- could serve as an insecticide.

Language