Abstract
The a-Conotoxins are peptide toxins that are found in the venom of marine cone snails and they are potent antagonists of various subtypes of nicotinic acetylcholine receptors (nAChRs). Because nAChRs have an important role in regulating transmitter release, cell excitability, and neuronal integration, nAChR dysfunctions have been implicated in a variety of severe pathologies. We describe the isolation and characterization of α-conotoxin MilIA, the first conopeptide from the venom of Conus milneedwardsi. The peptide was characterized by electrophysiological screening against several types of cloned nAChRs that were expressed in Xenopus laevis oocytes. MilIA, which is a member of the α3/5 family, is an antagonist of muscle type nAChRs with a high selectivity for muscle versus neuronal subtype nAChRs. Several analogues were designed and investigated for their activity in order to determine the key epitopes of MilIA. Native MilIA and analogues both showed activity at the fetal muscle type nAChR. Two single mutations (Met9 and Asn10) allowed for MilIA to strongly discriminate between the two types of muscle nAChRs. Moreover, one analogue, MilIA [∆1,M2R, M9G, N10K, H11K], displayed a remarkable enhanced potency when compared to native peptide. The key residues that are responsible for switching between muscle and neuronal nAChRs preference were elucidated. Interestingly, the same analogue showed a preference for α9α10 nAChRs among the neuronal types.
Highlights
Cone snails developed a powerful and efficient biological strategy to capture their prey and to defend against potential predators in order to survive
We report the identification and characterization of a novel 3/5 α-conotoxin, MilIA from the venom of Conus milneedwardsi
Conus milneedwardsi is known as the glory of India, because of its remarkably beautiful shell (Figure 1)
Summary
Cone snails developed a powerful and efficient biological strategy to capture their prey and to defend against potential predators in order to survive. Cone snails are equipped with a sophisticated venom apparatus, wherein a cocktail of biologically active components is synthesized by epithelial cells lining the venom duct to overcome their relatively limited locomotory compared to other aquatic organisms [1]. It is known that the venom of each individual species consists of 50 to 200 conotoxins [3]. These conotoxins are secreted by the venom gland and injected into the prey via a radular tooth.
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