Abstract
Cone snails are a diverse group of predatory marine invertebrates that deploy remarkably complex venoms to rapidly paralyse worm, mollusc or fish prey. ω-Conotoxins are neurotoxic peptides from cone snail venoms that inhibit Cav2.2 voltage-gated calcium channel, demonstrating potential for pain management via intrathecal (IT) administration. Here, we isolated and characterized two novel ω-conotoxins, MoVIA and MoVIB from Conus moncuri, the first to be identified in vermivorous (worm-hunting) cone snails. MoVIA and MoVIB potently inhibited human Cav2.2 in fluorimetric assays and rat Cav2.2 in patch clamp studies, and both potently displaced radiolabeled ω-conotoxin GVIA (125I-GVIA) from human SH-SY5Y cells and fish brain membranes (IC50 2–9 pM). Intriguingly, an arginine at position 13 in MoVIA and MoVIB replaced the functionally critical tyrosine found in piscivorous ω-conotoxins. To investigate its role, we synthesized MoVIB-[R13Y] and MVIIA-[Y13R]. Interestingly, MVIIA-[Y13R] completely lost Cav2.2 activity and MoVIB-[R13Y] had reduced activity, indicating that Arg at position 13 was preferred in these vermivorous ω-conotoxins whereas tyrosine 13 is preferred in piscivorous ω-conotoxins. MoVIB reversed pain behavior in a rat neuropathic pain model, confirming that vermivorous cone snails are a new source of analgesic ω-conotoxins. Given vermivorous cone snails are ancestral to piscivorous species, our findings support the repurposing of defensive venom peptides in the evolution of piscivorous Conidae.
Highlights
Completely lost Cav2.2 activity and MoVIB-[R13Y] had reduced activity, indicating that Arg at position 13 was preferred in these vermivorous ω-conotoxins whereas tyrosine 13 is preferred in piscivorous ω-conotoxins
Most characterised conotoxins target ion channels in the peripheral and central nervous systems and muscle cells, providing a rich source of potent and selective molecules with potential to treat a variety of diseases, including pain3. ω-Conotoxin are a class of conopeptides in the knottin family that potently inhibit the mammalian neuronal Cav channels, including Cav2.23
Hunting cone snails, where they were initially proposed to contribute to the “motor cabal” of conotoxins evolved for predation[16] but more recently they have been identified as playing major defensive role[17]
Summary
Completely lost Cav2.2 activity and MoVIB-[R13Y] had reduced activity, indicating that Arg at position 13 was preferred in these vermivorous ω-conotoxins whereas tyrosine 13 is preferred in piscivorous ω-conotoxins. Given ω-conotoxins were hypothesized to be repurposed from a defensive role in ancestral worm hunting species that facilitated a shift to fish hunting[12], we used a Cav2.2 screen to identify two novel ω-conotoxins MoVIA and MoVIB in the venom of Conus moncuri, a western Pacific worm hunting (vermivorous) cone snail[18,19]. C. moncuri was initially considered a synonym of Conus litteratus (subgenus Elisaconus) but was recently recognized as a new species[20] and placed in the Embrikena subgenus[21] These new ω-conotoxins had an arginine at position 13 instead of a tyrosine previously shown to be crucial for ω-conotoxin activity[22,23] and both preferentially targeted fish Cav2.2, suggesting ω-conotoxins play a defensive role in vermivorous cone snail species[17]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
