Abstract
Cone snails produce a fast-acting and often paralyzing venom that is usually injected into their prey or predator through a hypodermic needle-like modified radula tooth. Many diverse compounds are found in their venom including small molecules, peptides and enzymes. However, peptidic toxins called conotoxins (10–40 residues and 2–4 disulfide bonds) largely dominate these cocktails. These disulfide rich toxins are very valuable pharmacological tools for investigating the function of ions channels, G-protein coupled receptors, transporters and enzymes. Here, we report on the synthesis, structure determination and biological activities of two α-conotoxins, CIA and CIB, found in the predatory venom of the piscivorous species Conus catus. CIA is a typical 3/5 α-conotoxin that blocks the rat muscle type nAChR with an IC50 of 5.7 nM. Interestingly, CIA also inhibits the neuronal rat nAChR subtype α3β2 with an IC50 of 2.06 μM. CIB is a 4/7 α-conotoxin that blocks rat neuronal nAChR subtypes, including α3β2 (IC50 = 128.9 nM) and α7 (IC50 = 1.51 μM). High resolution NMR structures revealed typical α-conotoxin folds for both peptides. We also investigated the in vivo effects of these toxins on fish, since both peptides were identified in the predatory venom of C. catus. Consistent with their pharmacology, CIA was highly paralytic to zebrafish (ED50 = 110 μg/kg), whereas CIB did not affect the mobility of the fish. In conclusion, CIA likely participates in prey capture through muscle paralysis, while the putative ecological role of CIB remains to be elucidated.
Highlights
Cone snails are predatory marine mollusks comprising more than 800 different species [1].They capture prey using a venom gland that produces a fast-acting paralyzing venom injected through a hypodermic needle-like radula tooth [2]
In order to determine the ecological role of α-conotoxins in other fish-hunting species, we report on the synthesis, structure determination and biological activities of two new α-conotoxins CIA and CIB
Duct extracts have traditionally been associated to primary roles in prey-capture due [2]. To their paralytic independently collected predation and defense-evoked venoms unexpectedly showed that the potent action, recent findings suggest other possible venom-ecology relationships [2]
Summary
Cone snails are predatory marine mollusks comprising more than 800 different species [1]. They capture prey using a venom gland that produces a fast-acting paralyzing venom injected through a hypodermic needle-like radula tooth [2]. Conotoxins often have highly specific and selective biological activity, and many of them proved to be very valuable pharmacological tools or even drug leads [6,7,8] Their high selectivity and affinity combined with their small size make these toxins good candidates for the design of therapeutic peptides or peptide mimetics [9,10]. One particular class of conotoxins, the α-conotoxins, acts as antagonists of the nicotinic acetylcholine receptors (nAChRs), a diverse family of ligand-gated ion channels formed by the pentameric assembly of homologous subunits [8]
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