Abstract
GABAA-receptors (GABARs) are chloride ion channels in the ‘cys-loop receptor’ superfamily that are major inhibitory neuroreceptors. Upon agonist binding, GABARs open and increase intraneuronal chloride ion concentration, hyperpolarize the cell and inhibit neural transmission. Reducing agents will break the disulfide bonds in the cys-loop of the receptor. Indeed, it has been speculated that sulfhydryl compounds modify proteins via thiol/disulfide redox reactions and serve as neuromodulators (1). Reducing reagents were found to decrease the GABA EC50 in the highly homologous GABAC-receptor, while oxidizing reagents increased the EC50 (2). Conversely, conflicting findings suggests the mechanism of action of redox modulation does not alter GABAR agonist-binding affinity (3). However, studies are complicated by the fact that mutagenesis of the cysteines commonly produces failure of subunit assembly (4). Thus, to investigate the effect of disulfide bond breakage on the receptor we generated various GABAR homology models with and without disulfide bonds. These systems were subjected to ligand docking and extensive molecular dynamics simulations to determine if the GABA affinity was modulated. This work performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344.1. Allan, A. M. and L. D. Baier. 1992. Effect of thiol group modification on ion flux and ligand binding properties of the GABAA-benzodiazepine receptor chloride channel complex. Synapse 10:310-316.2. Calero, C. I. and D. J. Calvo. 2008. Redox modulation of homomeric rho1 GABA receptors. J Neurochem 105:2367-2374.3. Pan, Z. H., et al. 2000. Redox modulation of recombinant human GABA(A) receptors. Neuroscience 98:333-338.4. Amin, J., et al. 1994. The agonist binding site of the gamma-aminobutyric acid type A channel is not formed by the extracellular cysteine loop. Mol Pharmacol 45:317-323.LLNL-ABS-502871
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