Citation

Cherki RS, Kolb E, Langut Y, Tsveyer L, Bajayo N, Meir A. Toxicon 2014; 77: 58-67.

Affiliation

Alomone Labs Ltd, PO Box 4287, Jerusalem, Israel.

Copyright

(Copyright © 2014, Elsevier Publishing)

DOI

10.1016/j.toxicon.2013.10.029

PMID

24211312

Abstract

Voltage dependent sodium (NaV) channels are large membrane spanning proteins which lie in the basis of action potential generation and propagation in excitable cells and hence are essential mediators of neuronal signaling. Inhibition of NaV channel activity is one of the core mechanisms to treat conditions related to neuronal hyperexcitability, such as epilepsy in the clinic. NaV channel blockers are also extensively used to locally inhibit action potential generation and related pain perceptions in the form of local anesthetics. Here we describe the isolation, biochemical characterization, synthesis and in vitro characterization of two potent NaV channel blockers from the venom of the Paraphysa scrofa (Phrixotrichus auratus) tarantula spider. Both Voltage sensor toxin 3 (VSTx-3, κ-theraphotoxin-Gr4a) and GTx1-15 (Toxin Gtx1-15), were originally isolated from the venom of the related tarantula Grammostola rosea and described as KV and CaV channel blockers, respectively. In our hands, GTx1-15 was shown to be a potent inhibitor of tetrodotoxin (TTX)-sensitive channels (IC50 0.007 μM for hNaV1.7 and 0.12 μM for hNaV1.3 channels), with very little effect on TTX-resistant (NaV1.5 and NaV1.8) channels. VSTx-3 was demonstrated to be a potent, TTX-sensitive sodium channel blocker and especially, potent blocker of NaV1.8 channels (IC50 0.19 μM for hNaV1.3, 0.43 μM for hNaV1.7 and 0.77 μM for hNaV1.8 channels). Such potent inhibitors with differential selectivity among NaV channel isoforms may be used as tools to study the roles of the different channels in processes related to hyperexcitability and as lead compounds to treat pathological pain conditions.

Language: en