Abstract
A novel peptide, RsXXIVA, was isolated from the venom duct of Conus regularis, a worm-hunting species collected in the Sea of Cortez, México. Its primary structure was determined by mass spectrometry and confirmed by automated Edman degradation. This conotoxin contains 40 amino acids and exhibits a novel arrangement of eight cysteine residues (C-C-C-C-CC-CC). Surprisingly, two loops of the novel peptide are highly identical to the amino acids sequence of ω-MVIIA. The total length and disulfide pairing of both peptides are quite different, although the two most important residues for the described function of ω-MVIIA (Lys2 and Tyr13) are also present in the peptide reported here. Electrophysiological analysis using superior cervical ganglion (SCG) neurons indicates that RsXXIVA inhibits CaV2.2 channel current in a dose-dependent manner with an EC50 of 2.8 μM, whose effect is partially reversed after washing. Furthermore, RsXXIVA was tested in hot-plate assays to measure the potential anti-nociceptive effect to an acute thermal stimulus, showing an analgesic effect in acute thermal pain at 30 and 45 min post-injection. Also, the toxin shows an anti-nociceptive effect in a formalin chronic pain test. However, the low affinity for CaV2.2 suggests that the primary target of the peptide could be different from that of ω-MVIIA.
Highlights
Conotoxins from cone snails are interesting molecules with a diverse human therapeutic potential, such as anti-nociceptive, antiepileptic, cardio- and neuro-protective activity [1]
Based on the nomenclature of Olivera and Cruz [16], this conotoxin was named RsXXIVA, where ―Rs‖ refers to the specie’s name, C. regularis, the number, ―XXIV‖, specifies the type of Cys framework (C-C-C-C-CC-CC) and ―A‖ stands for the letter assigned to the first peptide isolated within this new cysteine framework
Compared to the block with 100 μM Cd2+. These results show that the toxin RsXXIVA inhibits CaV2.2 channels, despite its different cysteine framework, and it is partially reversible
Summary
Conotoxins from cone snails are interesting molecules with a diverse human therapeutic potential, such as anti-nociceptive, antiepileptic, cardio- and neuro-protective activity [1] They have become useful tools for research into cancer, neuromuscular and psychiatric disorders [2]. The assessment of the genus Conus is the largest single genus of venomous animals known, with around 700 species; considering the fact that each species could express between 100 and 200 venom peptides, it has been estimated that the number of different peptides that can be expressed is at least 70,000 [3] This could be translated to a surprising amount of different molecules that have been or will be discovered for different molecular targets. We propose a new cysteine family framework, which should correspond to the number XXIV, according to the conotoxin family nomenclature [6,7,8]
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