Journal article
Discovery and mode of action of a novel analgesic β-toxin from the African spider Ceratogyrus darlingi
PLoS One, Vol.12(9), e0182848
2017
Abstract
Spider venoms are rich sources of peptidic ion channel modulators with important therapeu-tical potential. We screened a panel of 60 spider venoms to find modulators of ion channels involved in pain transmission. We isolated, synthesized and pharmacologically characterized Cd1a, a novel peptide from the venom of the spider Ceratogyrus darlingi. Cd1a reversibly paralysed sheep blowflies (PD50 of 1318 pmol/g) and inhibited human Cav2.2 (IC50 2.6 μM) but not Cav1.3 or Cav3.1 (IC50 > 30 μM) in fluorimetric assays. In patch-clamp electrophysiological assays Cd1a inhibited rat Cav2.2 with similar potency (IC50 3 μM) without influencing the voltage dependence of Cav2.2 activation gating, suggesting that Cd1a doesn't act on Cav2.2 as a classical gating modifier toxin. The Cd1a binding site on Cav2.2 did not overlap with that of the pore blocker ω-conotoxin GVIA, but its activity at Cav2.2mutant indicated that Cd1a shares some molecular determinants with GVIA and MVIIA, localized near the pore region. Cd1a also inhibited human Nav1.1-1.2 and Nav1.7-1.8 (IC50 0.1-6.9 μM) but not Nav1.3-1.6 (IC50 > 30 μM) in fluorimetric assays. In patch-clamp assays, Cd1a strongly inhibited human Nav1.7 (IC50 16 nM) and produced a 29 mV depolarising shift in Nav1.7 voltage dependence of activation. Cd1a (400 pmol) fully reversed Nav1.7-evoked pain behaviours in mice without producing side effects. In conclusion, Cd1a inhibited two anti-nociceptive targets, appearing to interfere with Cav2.2 inactivation gating, associated with the Cav2.2 α-subunit pore, while altering the activation gating of Nav1.7. Cd1a was inactive at some of the Nav and Cav channels expressed in skeletal and cardiac muscles and nodes of Ranvier, apparently contributing to the lack of side effects at efficacious doses, and suggesting potential as a lead for development of peripheral pain treatments.
Details
- Title
- Discovery and mode of action of a novel analgesic β-toxin from the African spider Ceratogyrus darlingi
- Authors
- S R Sousa (Author) - University of QueenslandJ S Wingerd (Author) - University of QueenslandA Brust (Author) - University of QueenslandC Bladen (Author) - University of Calgary, CanadaL Ragnarsson (Author) - University of QueenslandVolker Herzig (Author) - University of QueenslandJ R Deuis (Author) - University of QueenslandS Dutertre (Author)I Vetter (Author) - University of QueenslandG W Zamponi (Author) - University of Calgary, CanadaG F King (Author) - University of QueenslandP F Alewood (Author) - University of QueenslandR J Lewis (Author) - University of Queensland
- Publication details
- PLoS One, Vol.12(9), e0182848; 22
- Publisher
- Public Library of Science
- Date published
- 2017
- DOI
- 10.1371/journal.pone.0182848
- ISSN
- 1932-6203; 1932-6203
- Copyright note
- Copyright © 2017 Sousa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
- Organisation Unit
- School of Science and Engineering - Legacy; University of the Sunshine Coast, Queensland; School of Science, Technology and Engineering; Centre for Bioinnovation
- Language
- English
- Record Identifier
- 99450848502621
- Output Type
- Journal article
- Research Statement
- false
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