Abstract
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.
Highlights
Symmetry pervades nature at all levels from nuclear physics to astronomy [1]
Compounds 1–4 were tested for inhibition of recombinant a1b2c2 GABAA receptors
We have identified an aromatic monovalent anion with five-fold symmetry, PCCP2, as inhibitor of rat GABAA receptors
Summary
Symmetry pervades nature at all levels from nuclear physics to astronomy [1]. In biology, it enables complex functions to arise from a limited set of building blocks and associated genes. A case in point is protein assemblies, such as viral capsids or transmembrane ion channels. The former often show icosahedral symmetry, allowing for the encapsulation of maximum space with a minimum number of protein components [2]. The latter are often multimeric, for instance tetrameric (voltage-gated potassium channels), pentameric (cys-loop receptors) or hexameric (Orai channels), with a central pore formed by membrane-spanning subunits. Following the establishment of a basic multimeric assembly early in evolution, a higher level of functional sophistication is sometimes achieved through subsequent desymmetrization, for instance through concatenation or heteromultimerization of closely related, yet distinct, subunits
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