Identification of a mammalian target of kappaM-conotoxin RIIIK.
Despite the great variability of the conus peptides characterized until now only relatively few have been identified that interact with K+ channels. kappaM-conotoxin RIIIK (kappaM-RIIIK) is a 24 amino acid peptide from Conus radiatus, which is structurally similar to micro-conotoxin GIIIA, a peptide known to block specifically skeletal muscle Na+ channels. Recently, it has been shown that kappaM-RIIIK does not interact with Na) channels, but inhibits Shaker potassium channels expressed in Xenopus oocytes. It was demonstrated that kappaM-RIIIK binds to the pore region of Shaker channels and a teleost homologue of the Shaker channel TSha1 was identified as a high affinity target of the toxin. In contrast the mammalian Shaker-homologues Kv1.1, Kv1.3, Kv1.4 are not affected by the toxin. In this study the activity of kappaM-RIIIK on other mammalian Kv1 K+ channels expressed in Xenopus oocytes was investigated. We demonstrate that kappaM-conotoxin RIIIK up to 5 microM exhibits no significant effect on Kv1.5 and Kv1.6 mediated currents, but the human Kv1.2 K+ channel is blocked by this peptide. The binding of kappaM-RIIIK to Kv1.2 channels is state dependent with an IC50 for the closed state of about 200 nM and for the open state of about 400 nM at a test potential of 0 mV. kappaM-conotoxin RIIIK is the first conotoxin described to block human Kv1.2 potassium channels.
Ferber
Michael
M
AG Molekulare und Zelluläre Neuropharmakologie, Max-Planck-Institut für Experimentelle Medizin, Hermann-Rein-Strasse 3, D-37075 Göttingen, Germany.
Al-Sabi
Ahmed
A
Stocker
Martin
M
Olivera
Baldomero M
BM
Terlau
Heinrich
H
D000818:Animals; D020916:Conotoxins / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006801:Humans; D007700:Kinetics; D051663:Kv1.2 Potassium Channel; D026902:Potassium Channel Blockers / Q000378:metabolism / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D051637:Shaker Superfamily of Potassium Channels; D012908:Snails / Q000737:chemistry*; D014981:Xenopus / Q000378:metabolism
D020916:Conotoxins; C496969:KCNA2 protein, human; D051663:Kv1.2 Potassium Channel; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051637:Shaker Superfamily of Potassium Channels; C471553:kappaM-conotoxin RIIIK, Conus radiatus