Crotamine Pharmacology Revisited: Novel Insights Based on the Inhibition of K-V Channels

Author(s)

Peigneur, Steve ^[1] ; Orts, Diego J. B. ^[2] ; Prieto da Silva, Alvaro R. ^[3] ; Oguiura, Nancy ^[4] ; Boni-Mitake, Malvina ^[5] ; de Oliveira, Eduardo B. ^[6] ; Zaharenko, Andre J. ^[3] ; de Freitas, Jose C. ^[2] ; Tytgat, Jan ^[1]

Affiliation

^[1] Katholieke Univ Leuven, Toxicol Lab, Louvain - Belgium

^[2] Univ Sao Paulo, Inst Biociencias, Dept Fisiol, Sao Paulo - Brazil

^[3] Inst Butantan, Genet Lab, Sao Paulo - Brazil

^[4] Inst Butantan, Lab Ecol & Evolucao, Sao Paulo - Brazil

^[5] Comissao Nacl Energia Nucl, Inst Pesquisas Energet & Nucl, Sao Paulo - Brazil

^[6] Univ Sao Paulo, Dept Biochem & Immunol, Ribeirao Preto Med Sch, Sao Paulo - Brazil

• Document type: Journal article
• Source: MOLECULAR PHARMACOLOGY; v. 82, n. 1, p. 90-96, JUL 2012.
• Web of Science Citations: 32

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 IC50 of similar to 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. (AU)

• FAPESP's process: 09/07128-7 - Sea anemones neurotoxins as tools to study the physiology of voltage-gated potassium channels
• Grantee: Diego Jose Orts y Belato
• Support Opportunities: Scholarships in Brazil - Master