AbeTx1 Is a Novel Sea Anemone Toxin with a Dual Mechanism of Action on Shaker-Type K+ Channels Activation

Autor(es)

Orts, Diego J. B. ^[1] ; Peigneur, Steve ^[2] ; Silva-Goncalves, Laiz Costa ^[3] ; Arcisio-Miranda, Manoel ^[3] ; Bicudo, Jose Eduardo P. W. ^[1] ; Tytgat, Jan ^[2]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biosci, Dept Physiol, BR-05508090 Sao Paulo - Brazil

^[2] Univ Leuven KU Leuven, Toxicol & Pharmacol, Campus Gasthuisberg O&N2, Herestr 49, POB 922, B-3000 Leuven - Belgium

^[3] Univ Fed Sao Paulo, Dept Biofis, Lab Neurobiol Estrut & Func LaNEF, BR-04023062 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: MARINE DRUGS; v. 16, n. 10 OCT 2018.
• Citações Web of Science: 2

Resumo

Voltage-gated potassium (K-V) channels regulate diverse physiological processes and are an important target for developing novel therapeutic approaches. Sea anemone (Cnidaria, Anthozoa) venoms comprise a highly complex mixture of peptide toxins with diverse and selective pharmacology on K-V channels. From the nematocysts of the sea anemone Actinia bermudensis, a peptide that we named AbeTx1 was purified and functionally characterized on 12 different subtypes of K-V channels (K(V)1.1-K(V)1.6; K(V)2.1; K(V)3.1; K(V)4.2; K(V)4.3; K(V)11.1; and, Shaker IR), and three voltage-gated sodium channel isoforms (Na(V)1.2, Na(V)1.4, and BgNa(V)). AbeTx1 was selective for Shaker-related K+ channels and is capable of inhibiting K+ currents, not only by blocking the K+ current of K(V)1.2 subtype, but by altering the energetics of activation of K(V)1.1 and K(V)1.6. Moreover, experiments using six synthetic alanine point-mutated analogs further showed that a ring of basic amino acids acts as a multipoint interaction for the binding of the toxin to the channel. The AbeTx1 primary sequence is composed of 17 amino acids with a high proportion of lysines and arginines, including two disulfide bridges (Cys1-Cys4 and Cys2-Cys3), and it is devoid of aromatic or aliphatic amino acids. Secondary structure analysis reveals that AbeTx1 has a highly flexible, random-coil-like conformation, but with a tendency of structuring in the beta sheet. Its overall structure is similar to open-ended cyclic peptides found on the scorpion -KTx toxins family, cone snail venoms, and antimicrobial peptides. (AU)

• Processo FAPESP: 16/13368-4 - Sistemas nanoestruturados: de modelos biomiméticos de membranas a carreadores de bioativos
• Beneficiário: Karin Do Amaral Riske
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 16/17951-6 - OBSERVANDO O pH INTRACELULAR DE CÉLULAS DA MICRÓGLIA
• Beneficiário: Manoel de Arcisio Miranda Filho
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 09/07128-7 - Neurotoxinas de anêmonas do mar como ferramentas para o estudo da fisiologia de canais voltagem - dependentes de potássio
• Beneficiário: Diego Jose Orts y Belato
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 11/21031-6 - Análise do mecanismo de ação envolvido na seletividade da atividade do peptídeo Abe III 1.3 em canais voltagem-dependentes de K+
• Beneficiário: Diego Jose Orts y Belato
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Mestrado