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Mar. Drugs 2018, 16(10), 360; https://doi.org/10.3390/md16100360

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

1
Department of Physiology, Institute of Biosciences, University of São Paulo, 05508-090 São Paulo, Brazil
2
Toxicology and Pharmacology, University of Leuven (KU Leuven), Campus Gasthuisberg O&N2, Herestraat 49, P.O. Box 922, 3000 Leuven, Belgium
3
Laboratório de Neurobiologia Estrutural e Funcional (LaNEF), Departamento de Biofísica, Universidade Federal de São Paulo, 04023-062 São Paulo, Brazil
*
Author to whom correspondence should be addressed.
Received: 31 August 2018 / Revised: 25 September 2018 / Accepted: 29 September 2018 / Published: 1 October 2018
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Abstract

Voltage-gated potassium (KV) 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 KV 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 KV channels (KV1.1–KV1.6; KV2.1; KV3.1; KV4.2; KV4.3; KV11.1; and, Shaker IR), and three voltage-gated sodium channel isoforms (NaV1.2, NaV1.4, and BgNaV). AbeTx1 was selective for Shaker-related K+ channels and is capable of inhibiting K+ currents, not only by blocking the K+ current of KV1.2 subtype, but by altering the energetics of activation of KV1.1 and KV1.6. 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 κ-KTx toxins family, cone snail venoms, and antimicrobial peptides. View Full-Text
Keywords: sea anemone neurotoxin; Actinia bermudensis; potassium channel; type 6 KV-toxins; Alanine point mutation sea anemone neurotoxin; Actinia bermudensis; potassium channel; type 6 KV-toxins; Alanine point mutation
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B. Orts, D.J.; Peigneur, S.; Silva-Gonçalves, L.C.; Arcisio-Miranda, M.; P. W. Bicudo, J.E.; Tytgat, J. AbeTx1 Is a Novel Sea Anemone Toxin with a Dual Mechanism of Action on Shaker-Type K+ Channels Activation. Mar. Drugs 2018, 16, 360.

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