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Novel analgesic ω-conotoxins from the vermivorous cone snail Conus moncuri provide new insights into the evolution of conopeptides

Journal Article


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 (IC502–9 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.

Authors


  •   Sousa, Silmara (external author)
  •   McArthur, Jeff R.
  •   Brust, Andreas (external author)
  •   Bhola, Rebecca (external author)
  •   Rosengren, K. . Johan (external author)
  •   Ragnarsson, L (external author)
  •   Dutertre, Sebastien (external author)
  •   Alewood, Paul F. (external author)
  •   Christie, MacDonald J. (external author)
  •   Adams, David J.
  •   Vetter, Irina (external author)
  •   Lewis, Richard J. (external author)

Publication Date


  • 2018

Citation


  • Sousa, S. R., McArthur, J. R., Brust, A., Bhola, R. F., Rosengren, K., Ragnarsson, L., Dutertre, S., Alewood, P. F., Christie, M. J., Adams, D. J., Vetter, I. & Lewis, R. J. (2018). Novel analgesic ω-conotoxins from the vermivorous cone snail Conus moncuri provide new insights into the evolution of conopeptides. Scientific Reports, 8 (1), 13397-1-13397-15.

Scopus Eid


  • 2-s2.0-85053005884

Start Page


  • 13397-1

End Page


  • 13397-15

Volume


  • 8

Issue


  • 1

Place Of Publication


  • United Kingdom

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 (IC502–9 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.

Authors


  •   Sousa, Silmara (external author)
  •   McArthur, Jeff R.
  •   Brust, Andreas (external author)
  •   Bhola, Rebecca (external author)
  •   Rosengren, K. . Johan (external author)
  •   Ragnarsson, L (external author)
  •   Dutertre, Sebastien (external author)
  •   Alewood, Paul F. (external author)
  •   Christie, MacDonald J. (external author)
  •   Adams, David J.
  •   Vetter, Irina (external author)
  •   Lewis, Richard J. (external author)

Publication Date


  • 2018

Citation


  • Sousa, S. R., McArthur, J. R., Brust, A., Bhola, R. F., Rosengren, K., Ragnarsson, L., Dutertre, S., Alewood, P. F., Christie, M. J., Adams, D. J., Vetter, I. & Lewis, R. J. (2018). Novel analgesic ω-conotoxins from the vermivorous cone snail Conus moncuri provide new insights into the evolution of conopeptides. Scientific Reports, 8 (1), 13397-1-13397-15.

Scopus Eid


  • 2-s2.0-85053005884

Start Page


  • 13397-1

End Page


  • 13397-15

Volume


  • 8

Issue


  • 1

Place Of Publication


  • United Kingdom