A potent potassium channel blocker from Mesobuthus eupeus scorpion venom.
Scorpion venom-derived peptidyl toxins are valuable pharmacological tools for investigating the structure-function relationship of ion channels. Here, we report the purification, sequencing and functional characterization of a new K(+) channel blocker (MeuKTX) from the venom of the scorpion Mesobuthus eupeus. Effects of MeuKTX on ten cloned potassium channels in Xenopus oocytes were evaluated using two-electrode voltage-clamp recordings. MeuKTX is the orthologue of BmKTX (α-KTx3.6), a known Kv1.3 blocker from the scorpion Mesobuthus martensii, and classified as α-KTx3.13. MeuKTX potently blocks rKv1.1, rKv1.2 and hKv1.3 channels with 50% inhibitory concentration (IC(50)) of 203.15 ± 4.06 pM, 8.92 ± 2.3 nM and 171 ± 8.56 pM, respectively, but does not affect rKv1.4, rKv1.5, hKv3.1, rKv4.3, and hERG channels even at 2 μM concentration. At this high concentration, MeuKTX is also active on rKv1.6 and Shaker IR. Our results also demonstrate that MeuKTX and BmKTX have the same channel spectrum and similar pharmacological potency. Analysis of the structure-function relationships of α-KTx3 subfamily toxins allows us to recognize several key sites which may be useful for designing toxins with improved activity on hKv1.3, an attractive target for T-cell mediated autoimmune diseases.
Gao
Bin
B
Group of Animal Innate Immunity, State Key Laboratory of Integrated Management of Pest Insects & Rodents, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, Beijing 100101, China.
Peigneur
Steve
S
Tytgat
Jan
J
Zhu
Shunyi
S
D000595:Amino Acid Sequence; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D051663:Kv1.2 Potassium Channel / Q000235:genetics / Q000502:physiology; D051664:Kv1.3 Potassium Channel / Q000235:genetics / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D008845:Microinjections; D008969:Molecular Sequence Data; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D010802:Phylogeny; D026902:Potassium Channel Blockers / Q000145:classification / Q000302:isolation & purification / Q000494:pharmacology*; D018075:RNA, Complementary / Q000008:administration & dosage / Q000235:genetics; D051381:Rats; D012604:Scorpion Venoms / Q000235:genetics / Q000302:isolation & purification / Q000494:pharmacology*; D012605:Scorpions / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D014982:Xenopus laevis
D051663:Kv1.2 Potassium Channel; D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D018075:RNA, Complementary; D012604:Scorpion Venoms