Tetramine, A Cage Convulsant with Potential for Terrorism: Block of Human Recombinant alpha1beta3gamma2 GABAA Receptors

The convulsant toxin tetramethylenedisulfotetramine (tetramine; TETS) is believed to induce seizures by inhibition of GABAA receptors at a site similar to the binding site for picrotoxinin, which is suggested to be in the inner channel pore. However, the potency for functional block of mammalian GABAA receptors has not been determined and mode of block has not been defined. We used patch-clamp recording and fast solution application to characterize the actions of tetramine on human recombinant alpha1beta3gamma2 GABAA receptors stably expressed in HEK 293 cells. tetramine and picrotoxinin caused a concentration-dependent inhibition of GABA-evoked currents with IC50 values of 4.4 muM and 9.6 muM for 30 muM of GABA, and 3.5 muM and 18.2 muM for 5 muM of the agonist, respectively. Block by tetramine occurs fast and is fully reversible. The extent of block by both toxins was unaffected by GABA concentration within the range of 1-100 muM, indicating a noncompetitive blocking mechanism. Block was also unaffected within the physiological membrane potential range. tetramine failed to exhibit a use-dependent blockage as confirmed by pre-incubation experiments. Our results conclude that tetramine is capable of interacting with the resting receptors and that it is only as much as 5-fold more potent than picrotoxinin to block human alpha1beta3gamma2 GABAA receptors.