Abstract
Crotamine, a 5-kDa peptide, possesses a unique biological versatility. Not only has its cell-penetrating activity become of clinical interest but, moreover, its potential selective antitumor activity is of great pharmacological importance. In the past, several studies have attempted to elucidate the exact molecular target responsible for the crotamine-induced skeletal muscle spasm. The aim of this study was to investigate whether crotamine affects voltage-gated potassium (KV) channels in an effort to explain its in vivo effects. Crotamine was studied on ion channel function using the two-electrode voltage clamp technique on 16 cloned ion channels (12 KV channels and 4 NaV channels), expressed in Xenopus laevis oocytes. Crotamine selectively inhibits KV1.1, KV1.2, and KV1.3 channels with an IC50 of ∼300 nM, and the key amino acids responsible for this molecular interaction are suggested. Our results demonstrate for the first time that the symptoms, which are observed in the typical crotamine syndrome, may result from the inhibition of KV channels. The ability of crotamine to inhibit the potassium current through KV channels unravels it as the first snake peptide with the unique multifunctionality of cell-penetrating and antitumoral activity combined with KV channel-inhibiting properties. This new property of crotamine might explain some experimental observations and opens new perspectives on pharmacological uses.
Footnotes
↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
This work was supported in part by Fundação de Amparo à Pesquisa do Estado de São Paulo [Grant 2009/07128-7]; Programa de Apoio à Pós-graduação-Coordenação de Aperfeiçoamento de Pessoal de Nível Superior 2010 (Brazilian Government) (to D.J.B.O.); and Conselho Nacional de Desenvolvimento Científico e Tecnológico [Grant 490194/2007-9] (to J.d.C.F.). J.T. was supported by Fonds Wetenschappelijk Onderzoek Vlaanderen [Grants G.0257.08 and G.0330.06]; Onderzoeks Traject K.U. Leuven [Grant 05-64]; and Universitaire Attractie Pool 6/31 (Interuniversity Attraction Poles).
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
ABBREVIATIONS:
- TTX
- tetrodotoxin
- PDB
- Protein Data Bank
- r
- rat
- h
- human
- DTX
- dendrotoxins
- CSαβ
- cysteine-stabilized α-helix and β-sheet.
- Received February 9, 2012.
- Accepted April 12, 2012.
- Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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