title: Inhibition of A-type potassium current by the peptide toxin SNX-482.
abstract: SNX-482, a peptide toxin isolated from tarantula venom, has become widely used as an inhibitor of Cav2.3 voltage-gated calcium channels. Unexpectedly, we found that SNX-482 dramatically reduced the A-type potassium current in acutely dissociated dopamine neurons from mouse substantia nigra pars compacta. The inhibition persisted when calcium was replaced by cobalt, showing that it was not secondary to a reduction of calcium influx. Currents from cloned Kv4.3 channels expressed in HEK-293 cells were inhibited by SNX-482 with an IC50 of <3 nM, revealing substantially greater potency than for SNX-482 inhibition of Cav2.3 channels (IC50 20-60 nM). At sub-saturating concentrations, SNX-482 produced a depolarizing shift in the voltage dependence of activation of Kv4.3 channels and slowed activation kinetics. Similar effects were seen on gating of cloned Kv4.2 channels, but the inhibition was less pronounced and required higher toxin concentrations. These results reveal SNX-482 as the most potent inhibitor of Kv4.3 channels yet identified. Because of the effects on both Kv4.3 and Kv4.2 channels, caution is needed when interpreting the effects of SNX-482 on cells and circuits where these channels are present.
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Tilia
authors.initials: T
authors.lastname: Kimm
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115 bruce_bean@hms.harvard.edu.
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Bean
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000502:physiology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D051672:Shal Potassium Channels / Q000187:drug effects* / Q000502:physiology; D013111:Spider Venoms / Q000494:pharmacology*
chemical_list: D026902:Potassium Channel Blockers; C115521:SNX 482; D051672:Shal Potassium Channels; D013111:Spider Venoms; D011188:Potassium
keywords: Cav2.3; IA; ICK toxin; Kv4.2; Kv4.3; tarantula toxin