The GABA_A receptor antagonist picrotoxin inhibits 5-hydroxytryptamine type 3A receptors

For a number of years it has been known that the CNS convulsant picrotoxin inhibits the GABA_A receptor, an anion-selective member of the ligand-gated ion channel (LGIC) superfamily. PTX also inhibits other anion-selective LGIC members, such as GABA_C, glycine and glutamate-gated Cl^- channels. In the present report, we tested the ability of picrotoxin to inhibit cation-selective 5-HT_3A receptors. Murine 5-HT_3A receptors were expressed in HEK293 cells, and functionally evaluated using whole-cell patch clamp recording. Picrotoxin inhibited 5-HT-gated currents in a concentration-dependent manner, with an IC₅₀ of approximately 30 μM. Moreover, the blockade by PTX was non-competitive and use-facilitated. Pentylenetetrazole and U-93631, ligands that act at a domain similar to that of picrotoxin in GABA_A receptors, also inhibited the 5-HT_3A receptor. For each ligand tested, its potency was 5-10 fold lower than typically observed in GABA_A receptors. Our results demonstrate that, in addition to being a relatively non-selective inhibitor of anionic LGICs, picrotoxin also inhibits the cation-selective 5-HT_3A receptor. Moreover, the fact that both PTZ and U-93631 similarly inhibit the 5-HT_3A receptor is consistent with the suggestion that the site of picrotoxin action in this receptor may be comparable to that in anion-selective LGICs.