期刊
FASEB JOURNAL
卷 26, 期 12, 页码 5141-5151出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.12-218479
关键词
voltage-gated sodium channel; voltage-gated potassium channel; ion channel inhibitor; ion channel modulator
资金
- Fonds Wetenschappelijk Onderzoek Vlaanderen [G.0433.12]
- Inter-University Attraction Poles (IUAP) Program (Belgian State, Belgian Science Policy) [7/19]
- Katholieke Universiteit Leuven [OT/12/081]
APETx3, a novel peptide isolated from the sea anemone Anthopleura elegantissima, is a naturally occurring mutant from APETx1, only differing by a Thr to Pro substitution at position 3. APETx1 is believed to be a selective modulator of human ether-a-go-go related gene (hERG) potassium channels with a K-d of 34 nM. In this study, APETx1, 2, and 3 have been subjected to an electrophysiological screening on a wide range of 24 ion channels expressed in Xenopus laevis oocytes: 10 cloned voltage-gated sodium channels (Na-V 1.2-Na(V)1.8, the insect channels DmNa(V)1, BgNa(V)1-1a, and the arachnid channel VdNa(V)1) and 14 cloned voltage-gated potassium channels (K(V)1.1-K(V)1.6, K(V)2.1, K(V)3.1, K(V)4.2, K(V)4.3, K(V)7.2, K(V)7.4, hERG, and the insect channel Shaker IR). Surprisingly, the Thr3Pro substitution results in a complete abolishment of APETx3 modulation on hERG channels and provides this toxin the ability to become a potent (EC50 276 nM) modulator of voltage-gated sodium channels (Na(V)s) because it slows down the inactivation of mammalian and insect Na-V channels. Our study also shows that the homologous toxins APETx1 and APETx2 display promiscuous properties since they are also capable of recognizing Na-V channels with IC50 values of 31 nM and 114 nM, respectively, causing an inhibition of the sodium conductance without affecting the inactivation. Our results provide new insights in key residues that allow these sea anemone toxins to recognize distinct ion channels with similar potency but with different modulatory effects. Furthermore, we describe for the first time the target promiscuity of a family of sea anemone toxins thus far believed to be highly selective.-Peigneur, S., Beress, L., Moller, C., Mari, F., Forssmann, W.-G., Tytgat, J. A natural point mutation changes both target selectivity and mechanism of action of sea anemone toxins. FASEB J. 26, 5141-5151 (2012). www.fasebj.org
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