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- W2066911868 abstract "GABAA receptors (GABARs) couple GABA binding to opening of a chloride-conducting channel. The GABA binding site is at β/α-subunit interfaces. In a recent GABAR crystal structure, the β5-β5’ loop reaches across the interface, and juts into the neighboring subunit forming a back lid over the GABA binding site. This extended β5-β5’ loop conformation is not in prokaryotic channels, the acetylcholine-binding protein, or the nicotinic acetylcholine receptor. We used disulfide trapping to probe β5-β5’ loop position and dynamics in α1β2γ2L GABARs. We engineered pairs of cysteines at the β/α GABA-binding site interface: αM111C (β5-β5’ loop) with βS104C (β-strand 5) and α1M113C (β5-β5’ loop) with β2D95C (binding Region A). We expressed single and double mutant α1β2γ2L GABARs in Xenopus oocytes. Initially, we tested for disulfide-bonds by measuring effects of DTT and hydrogen peroxide on GABA-mediated currents from α1M111Cβ2S104Cγ2 and α1M113Cβ2D95Cγ2 receptors. They had no effects. Methanethiosulfonate reagents modified the single cysteine mutants but not the double mutants, indicating the cysteine pairs were linked by disulfides. Single-mutant α1β2S104Cγ2 receptors had reduced GABA efficacy and potency, which were rescued in double-mutant α1M111Cβ2S104Cγ2 receptors, suggesting the cysteines interact. These results indicate the α-subunit β5-β5’ loop extends across the intersubunit interface, near β-strand 5 of the β-subunit. Disulfide linking these two regions had no effect on GABA currents, indicating their relative positions do not change during GABA activation and supporting the idea of a concerted GABA-driven motion in the inner β-sheets of the α- and β-subunits. Linking cysteines in aligned positions at the benzodiazepine-binding α1/γ2-interface (α1S106C and γ2I124C) had similar effects. In contrast, tethering α1M113C (β5-β5’ loop) to β2D95C near Region A of the GABA binding site right-shifted GABA concentration-responses, suggesting this crosslink impairs motions in the site required for GABA action." @default.
- W2066911868 created "2016-06-24" @default.
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- W2066911868 date "2015-01-01" @default.
- W2066911868 modified "2023-09-30" @default.
- W2066911868 title "Disulfide Trapping the GABA-A Receptor Extracellular Beta-5/Beta-5’ Loop" @default.
- W2066911868 doi "https://doi.org/10.1016/j.bpj.2014.11.1061" @default.
- W2066911868 hasPublicationYear "2015" @default.
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