title: Crotamine pharmacology revisited: novel insights based on the inhibition of KV channels.
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 (K(V)) 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 K(V) channels and 4 Na(V) channels), expressed in Xenopus laevis oocytes. Crotamine selectively inhibits K(V)1.1, K(V)1.2, and K(V)1.3 channels with an IC(50) 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 K(V) channels. The ability of crotamine to inhibit the potassium current through K(V) channels unravels it as the first snake peptide with the unique multifunctionality of cell-penetrating and antitumoral activity combined with K(V) channel-inhibiting properties. This new property of crotamine might explain some experimental observations and opens new perspectives on pharmacological uses.
authors.affiliation: Laboratory of Toxicology, University of Leuven (K.U. Leuven), Campus Gasthuisberg O&N2, Herestraat 49, P.O. Box 922, B-3000 Leuven, Belgium.
authors.forename: Steve
authors.initials: S
authors.lastname: Peigneur
authors.forename: Diego J B
authors.initials: DJ
authors.lastname: Orts
authors.forename: Alvaro R
authors.initials: AR
authors.lastname: Prieto da Silva
authors.forename: Nancy
authors.initials: N
authors.lastname: Oguiura
authors.forename: Malvina
authors.initials: M
authors.lastname: Boni-Mitake
authors.forename: Eduardo B
authors.initials: EB
authors.lastname: de Oliveira
authors.forename: André J
authors.initials: AJ
authors.lastname: Zaharenko
authors.forename: Jose C
authors.initials: JC
authors.lastname: de Freitas
authors.forename: Jan
authors.initials: J
authors.lastname: Tytgat
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology; D003435:Crotalid Venoms / Q000302:isolation & purification* / Q000494:pharmacology*; D017839:Crotalus; D009865:Oocytes / Q000378:metabolism; D010455:Peptides / Q000302:isolation & purification / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D000970:Antineoplastic Agents; D003435:Crotalid Venoms; D010455:Peptides; D024642:Potassium Channels, Voltage-Gated; C010563:crotamine