Voltage-sensor conformation shapes the intra-membrane drug binding site that determines gambierol affinity in Kv channels

NEUROPHARMACOLOGY

卷:107

Article

Kopljar, Ivan^1,5  Grottesi, Alessandro²  de Block, Tessa¹  Rainier, Jon D.³  Tytgat, Jan⁴  Labro, Alain J.¹  Snyders, Dirk J.¹ 

[1] Univ Antwerp, Lab Mol Biophys Physiol & Pharmacol, B-2610 Antwerp, Belgium

[2] CINECA, Sede Roma, Via Tizii 6, I-00185 Rome, Italy

[3] Univ Utah, Dept Chem, Salt Lake City, UT 84112 USA

[4] Univ Leuven, Toxicol & Pharmacol, Campus Gasthuisberg, B-3000 Leuven, Belgium

[5] Janssen Res & Dev, Global Safety Pharmacol, PD&S, Discovery Sci, Beerse, Belgium

关键词: Voltage-gated potassium channel;    Electrophysiology;    Gating modifier;    Polycyclic ether toxin;    Ciguatoxins;   

DOI  :  10.1016/j.neuropharm.2016.03.010

来源: Elsevier

【 摘 要 】

Marine ladder-shaped polyether toxins are implicated in neurological symptoms of fish-borne food poisonings. The toxin gambierol, produced by the marine dinoflagellate Gambierdiscus toxicus, belongs to the group of ladder-shaped polyether toxins and inhibits Kv3.1 channels with nanomolar affinity through a mechanism of gating modification. Binding determinants for gambierol localize at the lipid-exposed interface of the pore forming S5 and S6 segments, suggesting that gambierol binds outside of the permeation pathway. To explore a possible involvement of the voltage-sensing domain (VSD), we made different chimeric channels between Kv3.1 and Kv2.1, exchanging distinct parts of the gating machinery. Our results showed that neither the electro-mechanical coupling nor the S1-S3a region of the VSD affect gambierol sensitivity. In contrast, the S3b-S4 part of the VSD (paddle motif) decreased gambierol sensitivity in Kv3.1 more than 100-fold. Structure determination by homology modeling indicated that the position of the S3b-S4 paddle and its primary structure defines the shape and\or the accessibility of the binding site for gambierol, explaining the observed differences in gambierol affinity between the channel chimeras. Furthermore, these findings explain the observed difference in gambierol affinity for the closed and open channel configurations of Kv3.1, opening new possibilities for exploring the VSDs as selectivity determinants in drug design. (C) 2016 Elsevier Ltd. All rights reserved.

【 授权许可】

Free