In: PLOS ONE
9(9), e106688
[PDF, 1MB]
Abstract
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.
Item Type: | Journal article |
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Faculties: | Chemistry and Pharmacy > Department of Chemistry |
Subjects: | 500 Science > 540 Chemistry |
URN: | urn:nbn:de:bvb:19-epub-33446-6 |
ISSN: | 1932-6203 |
Language: | English |
Item ID: | 33446 |
Date Deposited: | 15. Feb 2017, 14:44 |
Last Modified: | 04. Nov 2020, 13:11 |