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.
Highlights
Voltage-gated potassium (KV ) channels regulate diverse physiological processes, including action potential duration, neuronal excitability, and neurotransmitter release
A. bermudensis venom was fractionated on a Sephadex G-50 column
Circular dichroism spectra of AbeTx1 activity, we looked for its intrinsic secondary structure
Summary
Voltage-gated potassium (KV ) channels regulate diverse physiological processes, including action potential duration, neuronal excitability, and neurotransmitter release. More than 50 human genes encoding 12 different families of KV channels have been cloned and their structure and biochemical properties characterized. Because of the importance of mutations that are associated with pathological disorders, KV channels have become an important target for developing novel therapeutic approaches and for drug design [1,2]. Since the early 19700 s, toxins have become essential tools in pharmacological and biochemical studies on KV channels, and from on, an increasing number of peptide neurotoxins that target these channels have been discovered [3,4]. Mar. Drugs 2018, 16, 360; doi:10.3390/md16100360 www.mdpi.com/journal/marinedrugs
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