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The pharmacological profile of ELIC, a prokaryotic GABA-gated receptor

The Erwinia ligand-gated ion channel (ELIC) is a bacterial homologue of vertebrate Cys-loop ligand-gated ion channels. It is activated by GABA, and this property, combined with its structural similarity to GABA(A) and other Cys-loop receptors, makes it potentially an excellent model to probe their s...

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Autores principales: Thompson, Andrew J., Alqazzaz, Mona, Ulens, Chris, Lummis, Sarah C.R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Pergamon Press 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3430861/
https://www.ncbi.nlm.nih.gov/pubmed/22677470
http://dx.doi.org/10.1016/j.neuropharm.2012.05.027
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author Thompson, Andrew J.
Alqazzaz, Mona
Ulens, Chris
Lummis, Sarah C.R.
author_facet Thompson, Andrew J.
Alqazzaz, Mona
Ulens, Chris
Lummis, Sarah C.R.
author_sort Thompson, Andrew J.
collection PubMed
description The Erwinia ligand-gated ion channel (ELIC) is a bacterial homologue of vertebrate Cys-loop ligand-gated ion channels. It is activated by GABA, and this property, combined with its structural similarity to GABA(A) and other Cys-loop receptors, makes it potentially an excellent model to probe their structure and function. Here we characterise the pharmacological profile of ELIC, examining the effects of compounds that could activate or inhibit the receptor. We confirm that a range of amino acids and classic GABA(A) receptor agonists do not elicit responses in ELIC, and we show the receptor can be at least partially activated by 5-aminovaleric acid and γ-hydroxybutyric acid, which are weak agonists. A range of GABA(A) receptor non-competitive antagonists inhibit GABA-elicited ELIC responses including α-endosulfan (IC(50) = 17 μM), dieldrin (IC(50) = 66 μM), and picrotoxinin (IC(50) = 96 μM) which were the most potent. Docking suggested possible interactions at the 2′ and 6′ pore-lining residues, and mutagenesis of these residues supports this hypothesis for α-endosulfan. A selection of compounds that act at Cys-loop and other receptors also showed some efficacy at blocking ELIC responses, but most were of low potency (IC(50) > 100 μM). Overall our data show that a number of compounds can inhibit ELIC, but it has limited pharmacological similarity to GLIC and to Cys-loop receptors.
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spelling pubmed-34308612012-09-05 The pharmacological profile of ELIC, a prokaryotic GABA-gated receptor Thompson, Andrew J. Alqazzaz, Mona Ulens, Chris Lummis, Sarah C.R. Neuropharmacology Article The Erwinia ligand-gated ion channel (ELIC) is a bacterial homologue of vertebrate Cys-loop ligand-gated ion channels. It is activated by GABA, and this property, combined with its structural similarity to GABA(A) and other Cys-loop receptors, makes it potentially an excellent model to probe their structure and function. Here we characterise the pharmacological profile of ELIC, examining the effects of compounds that could activate or inhibit the receptor. We confirm that a range of amino acids and classic GABA(A) receptor agonists do not elicit responses in ELIC, and we show the receptor can be at least partially activated by 5-aminovaleric acid and γ-hydroxybutyric acid, which are weak agonists. A range of GABA(A) receptor non-competitive antagonists inhibit GABA-elicited ELIC responses including α-endosulfan (IC(50) = 17 μM), dieldrin (IC(50) = 66 μM), and picrotoxinin (IC(50) = 96 μM) which were the most potent. Docking suggested possible interactions at the 2′ and 6′ pore-lining residues, and mutagenesis of these residues supports this hypothesis for α-endosulfan. A selection of compounds that act at Cys-loop and other receptors also showed some efficacy at blocking ELIC responses, but most were of low potency (IC(50) > 100 μM). Overall our data show that a number of compounds can inhibit ELIC, but it has limited pharmacological similarity to GLIC and to Cys-loop receptors. Pergamon Press 2012-09 /pmc/articles/PMC3430861/ /pubmed/22677470 http://dx.doi.org/10.1016/j.neuropharm.2012.05.027 Text en © 2012 Elsevier Ltd. https://creativecommons.org/licenses/by/3.0/ Open Access under CC BY 3.0 (https://creativecommons.org/licenses/by/3.0/) license
spellingShingle Article
Thompson, Andrew J.
Alqazzaz, Mona
Ulens, Chris
Lummis, Sarah C.R.
The pharmacological profile of ELIC, a prokaryotic GABA-gated receptor
title The pharmacological profile of ELIC, a prokaryotic GABA-gated receptor
title_full The pharmacological profile of ELIC, a prokaryotic GABA-gated receptor
title_fullStr The pharmacological profile of ELIC, a prokaryotic GABA-gated receptor
title_full_unstemmed The pharmacological profile of ELIC, a prokaryotic GABA-gated receptor
title_short The pharmacological profile of ELIC, a prokaryotic GABA-gated receptor
title_sort pharmacological profile of elic, a prokaryotic gaba-gated receptor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3430861/
https://www.ncbi.nlm.nih.gov/pubmed/22677470
http://dx.doi.org/10.1016/j.neuropharm.2012.05.027
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