Abstract
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 GABAA receptors. To determine whether TETS exhibits subtype selectivity for a particular GABAA receptor combination, we used whole-cell patch-clamp to determine the potency of TETS on the major synaptic and extrasynaptic GABAA receptors associated with convulsant activity. The active component of picrotoxin, picrotoxinin, was used as a control. While picrotoxinin did not differentiate well between 13 GABAA receptors, TETS exhibited the highest activity on α2β3γ2 (IC50 480 nM, 95% CI 320–640 nM) and α6β3γ2 (IC50 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 GABAA receptors in the mammalian CNS, we suggest that α2β3γ2 is probably the most important GABAA receptor for the seizure-inducing activity of TETS.
Highlights
GABAA receptors are heteropentameric ligand-gated chloride channels that are activated by gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the adult CNS. GABAA receptors have a complex and often somewhat promiscuous pharmacology with numerous orthosteric and allosteric sites that modulate channel function (Krall et al 2015; Olsen 2015)
When comparing our EC50 values to the previous work in the field, we found that most of our results are in good agreement with data obtained by Mortson et al (2011), who transiently expressed various synaptic and extrasynaptic G ABAA receptors in HEK cells and reported a very similar overall ranking of GABA sensitivity
The rodenticide TETS has previously been primarily studied in animal models to assess its convulsant activity and toxicity or in binding assays, which demonstrated that TETS acts as a non-competitive G ABAA receptor inhibitor
Summary
GABAA receptors are heteropentameric ligand-gated chloride channels that are activated by gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the adult CNS. GABAA receptors have a complex and often somewhat promiscuous pharmacology with numerous orthosteric and allosteric sites that modulate channel function (Krall et al 2015; Olsen 2015). TETS (tetramethylenedisulfotetramine) and picrotoxin are both potent convulsants (Haskell and Voss 1957; Zolkowska et al 2012) that can cause severe tonic–clonic seizures and are, considered threat agents by the United States Department of Homeland Security. TETS has similar physicochemical properties, but is easy to synthesize, tasteless and odorless, and stable in drinking water for months (Knaack et al 2014) These characteristics make TETS a tangible threat
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