Effects of the ?-aminobutyric acid antagonist disulfotetraazaadamantane on evoked neuronal response in hippocampal slices

Pervukhin, G. Ya.; Шаронова, И. Н.; Prokof'ev, S. E.; Fedorov, N. A.; Kotel'nikov, S. A.; Fetisov, V. I.; Мартынов, И. В.

doi:10.1007/bf01059103

Cited by 1 publication

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“…However, so far, only very limited electrophysiological information is available for this highly toxic threat agent. In 1975, Bowery et al demonstrated that TETS could reverse the effects of GABA on isolated superior cervical rat ganglions at concentrations between 10 and 100 μM (Bowery et al 1975 ), while a group in the former Soviet Union showed in 1989 that 5 μM of TETS increased the excitability of hippocampal slices (Pervukhin et al 1989 ). A more recent paper from our own group describing the synthesis of TETS-related haptens for the development of an ELISA assay to detect TETS (Vasylieva et al 2017 ) reported that TETS inhibited chloride currents through α1β2γ2 GABA A receptors expressed in HEK293 cells with IC 50 of 8 μM (Barnych et al 2017 ).…”

Section: Discussionmentioning

confidence: 99%

GABAA receptor subtype selectivity of the proconvulsant rodenticide TETS

2017

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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 noncompetitive antagonist on GABAA receptors. To determine whether TETS exhibits subtype selectivity for a particular GABAA receptor combination, we used whole-cell patchclamp 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.

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