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 IC(50) of approximately 30 microM. 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.
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Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA.
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D000818:Animals; D002460:Cell Line; D018756:GABA Antagonists / Q000494:pharmacology*; D058787:GABA-A Receptor Antagonists; D006801:Humans; D008024:Ligands; D051379:Mice; D010433:Pentylenetetrazole / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000187:drug effects*; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists / Q000494:pharmacology*
D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D008024:Ligands; D010433:Pentylenetetrazole; D010852:Picrotoxin; D011810:Quinoxalines; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; C083857:U 93631