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GABA(A) receptor subtype selectivity of the proconvulsant rodenticide TETS

The rodenticide tetramethylenedisulfotetramine (TETS) is a potent convulsant (lethal dose in humans 7–10 mg) that is listed as a possible threat agent by the United States Department of Homeland Security. TETS has previously been studied in vivo for toxicity and in vitro in binding assays, with the...

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Autores principales: Pressly, Brandon, Nguyen, Hai M., Wulff, Heike
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818616/
https://www.ncbi.nlm.nih.gov/pubmed/29038840
http://dx.doi.org/10.1007/s00204-017-2089-4
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author Pressly, Brandon
Nguyen, Hai M.
Wulff, Heike
author_facet Pressly, Brandon
Nguyen, Hai M.
Wulff, Heike
author_sort Pressly, Brandon
collection PubMed
description The rodenticide tetramethylenedisulfotetramine (TETS) is a potent convulsant (lethal dose in humans 7–10 mg) that is listed as a possible threat agent by the United States Department of Homeland Security. TETS has previously been studied in vivo for toxicity and in vitro in binding assays, with the latter demonstrating it to be a non-competitive antagonist on GABA(A) receptors. To determine whether TETS exhibits subtype selectivity for a particular GABA(A) receptor combination, we used whole-cell patch-clamp to determine the potency of TETS on the major synaptic and extrasynaptic GABA(A) receptors associated with convulsant activity. The active component of picrotoxin, picrotoxinin, was used as a control. While picrotoxinin did not differentiate well between 13 GABA(A) receptors, TETS exhibited the highest activity on α2β3γ2 (IC(50) 480 nM, 95% CI 320–640 nM) and α6β3γ2 (IC(50) 400 nM, 95% CI 290–510 nM). Introducing β1 or β2 subunits into these receptor combinations reduced or abolished TETS sensitivity, suggesting that TETS preferentially affects receptors with α2/β3 or α6/β3 composition. Since α2β3γ2 receptors make up 15–20% of the GABA(A) receptors in the mammalian CNS, we suggest that α2β3γ2 is probably the most important GABA(A) receptor for the seizure-inducing activity of TETS.
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spelling pubmed-58186162018-02-21 GABA(A) receptor subtype selectivity of the proconvulsant rodenticide TETS Pressly, Brandon Nguyen, Hai M. Wulff, Heike Arch Toxicol Organ Toxicity and Mechanisms The rodenticide tetramethylenedisulfotetramine (TETS) is a potent convulsant (lethal dose in humans 7–10 mg) that is listed as a possible threat agent by the United States Department of Homeland Security. TETS has previously been studied in vivo for toxicity and in vitro in binding assays, with the latter demonstrating it to be a non-competitive antagonist on GABA(A) receptors. To determine whether TETS exhibits subtype selectivity for a particular GABA(A) receptor combination, we used whole-cell patch-clamp to determine the potency of TETS on the major synaptic and extrasynaptic GABA(A) receptors associated with convulsant activity. The active component of picrotoxin, picrotoxinin, was used as a control. While picrotoxinin did not differentiate well between 13 GABA(A) receptors, TETS exhibited the highest activity on α2β3γ2 (IC(50) 480 nM, 95% CI 320–640 nM) and α6β3γ2 (IC(50) 400 nM, 95% CI 290–510 nM). Introducing β1 or β2 subunits into these receptor combinations reduced or abolished TETS sensitivity, suggesting that TETS preferentially affects receptors with α2/β3 or α6/β3 composition. Since α2β3γ2 receptors make up 15–20% of the GABA(A) receptors in the mammalian CNS, we suggest that α2β3γ2 is probably the most important GABA(A) receptor for the seizure-inducing activity of TETS. Springer Berlin Heidelberg 2017-10-16 2018 /pmc/articles/PMC5818616/ /pubmed/29038840 http://dx.doi.org/10.1007/s00204-017-2089-4 Text en © The Author(s) 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Organ Toxicity and Mechanisms
Pressly, Brandon
Nguyen, Hai M.
Wulff, Heike
GABA(A) receptor subtype selectivity of the proconvulsant rodenticide TETS
title GABA(A) receptor subtype selectivity of the proconvulsant rodenticide TETS
title_full GABA(A) receptor subtype selectivity of the proconvulsant rodenticide TETS
title_fullStr GABA(A) receptor subtype selectivity of the proconvulsant rodenticide TETS
title_full_unstemmed GABA(A) receptor subtype selectivity of the proconvulsant rodenticide TETS
title_short GABA(A) receptor subtype selectivity of the proconvulsant rodenticide TETS
title_sort gaba(a) receptor subtype selectivity of the proconvulsant rodenticide tets
topic Organ Toxicity and Mechanisms
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818616/
https://www.ncbi.nlm.nih.gov/pubmed/29038840
http://dx.doi.org/10.1007/s00204-017-2089-4
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