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Discovery and mode of action of a novel analgesic β-toxin from the African spider Ceratogyrus darlingi.

Identifieur interne : 000501 ( PubMed/Curation ); précédent : 000500; suivant : 000502

Discovery and mode of action of a novel analgesic β-toxin from the African spider Ceratogyrus darlingi.

Auteurs : Silmara R. Sousa [Australie] ; Joshua S. Wingerd [Australie] ; Andreas Brust [Australie] ; Christopher Bladen [Canada] ; Lotten Ragnarsson [Australie] ; Volker Herzig [Australie] ; Jennifer R. Deuis [Australie] ; Sebastien Dutertre [France] ; Irina Vetter [Australie] ; Gerald W. Zamponi [Canada] ; Glenn F. King [Australie] ; Paul F. Alewood [Australie] ; Richard J. Lewis [Australie]

Source :

PloS one [ 1932-6203 ] ; 2017.

RBID : pubmed:28880874

Descripteurs français

KwdFr :
- Analgésiques (), Analgésiques (pharmacologie), Animaux, Araignées (), Canal sodique voltage-dépendant NAV1.1 (métabolisme), Canal sodique voltage-dépendant NAV1.7 (métabolisme), Canaux calciques de type N (métabolisme), Fluorimétrie, Humains, Peptides (), Peptides (pharmacologie), Rats, Sites de fixation (), Souris, Venins d'araignée (), Électrophysiologie.
MESH :
- métabolisme : Canal sodique voltage-dépendant NAV1.1, Canal sodique voltage-dépendant NAV1.7, Canaux calciques de type N.
- pharmacologie : Analgésiques, Peptides.
- Analgésiques, Animaux, Araignées, Fluorimétrie, Humains, Peptides, Rats, Sites de fixation, Souris, Venins d'araignée, Électrophysiologie.

English descriptors

KwdEn :
- Analgesics (chemistry), Analgesics (pharmacology), Animals, Binding Sites (drug effects), Calcium Channels, N-Type (metabolism), Electrophysiology, Fluorometry, Humans, Mice, NAV1.1 Voltage-Gated Sodium Channel (metabolism), NAV1.7 Voltage-Gated Sodium Channel (metabolism), Peptides (chemistry), Peptides (pharmacology), Rats, Spider Venoms (chemistry), Spiders (chemistry).
MESH :
- chemical , chemistry : Analgesics, Peptides, Spider Venoms.
- chemical , metabolism : Calcium Channels, N-Type, NAV1.1 Voltage-Gated Sodium Channel, NAV1.7 Voltage-Gated Sodium Channel.
- chemical , pharmacology : Analgesics, Peptides.
- chemistry : Spiders.
- drug effects : Binding Sites.
- Animals, Electrophysiology, Fluorometry, Humans, Mice, Rats.

Abstract

Spider venoms are rich sources of peptidic ion channel modulators with important therapeutical 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 Cav2.2-mutant 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.

DOI: 10.1371/journal.pone.0182848
PubMed: 28880874

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<term>Binding Sites (drug effects)</term>
<term>Calcium Channels, N-Type (metabolism)</term>
<term>Electrophysiology</term>
<term>Fluorometry</term>
<term>Humans</term>
<term>Mice</term>
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<term>Animaux</term>
<term>Araignées ()</term>
<term>Canal sodique voltage-dépendant NAV1.1 (métabolisme)</term>
<term>Canal sodique voltage-dépendant NAV1.7 (métabolisme)</term>
<term>Canaux calciques de type N (métabolisme)</term>
<term>Fluorimétrie</term>
<term>Humains</term>
<term>Peptides ()</term>
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<term>Rats</term>
<term>Sites de fixation ()</term>
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<term>Venins d'araignée ()</term>
<term>Électrophysiologie</term>
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<term>Peptides</term>
<term>Spider Venoms</term>
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<term>NAV1.1 Voltage-Gated Sodium Channel</term>
<term>NAV1.7 Voltage-Gated Sodium Channel</term>
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<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Analgesics</term>
<term>Peptides</term>
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<term>Canal sodique voltage-dépendant NAV1.7</term>
<term>Canaux calciques de type N</term>
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<term>Peptides</term>
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<term>Animaux</term>
<term>Araignées</term>
<term>Fluorimétrie</term>
<term>Humains</term>
<term>Peptides</term>
<term>Rats</term>
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<front><div type="abstract" xml:lang="en">Spider venoms are rich sources of peptidic ion channel modulators with important therapeutical 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 Cav2.2-mutant 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.</div>
</front>
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<Abstract><AbstractText>Spider venoms are rich sources of peptidic ion channel modulators with important therapeutical 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 Cav2.2-mutant 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.</AbstractText>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Sousa</LastName>
<ForeName>Silmara R</ForeName>
<Initials>SR</Initials>
<AffiliationInfo><Affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Wingerd</LastName>
<ForeName>Joshua S</ForeName>
<Initials>JS</Initials>
<AffiliationInfo><Affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Brust</LastName>
<ForeName>Andreas</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Bladen</LastName>
<ForeName>Christopher</ForeName>
<Initials>C</Initials>
<AffiliationInfo><Affiliation>Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, The University of Calgary, Calgary, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Ragnarsson</LastName>
<ForeName>Lotten</ForeName>
<Initials>L</Initials>
<AffiliationInfo><Affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Herzig</LastName>
<ForeName>Volker</ForeName>
<Initials>V</Initials>
<AffiliationInfo><Affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Deuis</LastName>
<ForeName>Jennifer R</ForeName>
<Initials>JR</Initials>
<AffiliationInfo><Affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Dutertre</LastName>
<ForeName>Sebastien</ForeName>
<Initials>S</Initials>
<AffiliationInfo><Affiliation>Institut des Biomolécules Max Mousseron, Université Montpellier - CNRS, Montpellier, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Vetter</LastName>
<ForeName>Irina</ForeName>
<Initials>I</Initials>
<AffiliationInfo><Affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>School of Pharmacy, The University of Queensland, Brisbane, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Zamponi</LastName>
<ForeName>Gerald W</ForeName>
<Initials>GW</Initials>
<AffiliationInfo><Affiliation>Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, The University of Calgary, Calgary, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>King</LastName>
<ForeName>Glenn F</ForeName>
<Initials>GF</Initials>
<AffiliationInfo><Affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Alewood</LastName>
<ForeName>Paul F</ForeName>
<Initials>PF</Initials>
<AffiliationInfo><Affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Lewis</LastName>
<ForeName>Richard J</ForeName>
<Initials>RJ</Initials>
<Identifier Source="ORCID">http://orcid.org/0000-0003-3470-923X</Identifier>
<AffiliationInfo><Affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.</Affiliation>
</AffiliationInfo>
</Author>
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<Language>eng</Language>
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</PublicationTypeList>
<ArticleDate DateType="Electronic"><Year>2017</Year>
<Month>09</Month>
<Day>07</Day>
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<MedlineTA>PLoS One</MedlineTA>
<NlmUniqueID>101285081</NlmUniqueID>
<ISSNLinking>1932-6203</ISSNLinking>
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<NameOfSubstance UI="C503279">Cacna1b protein, rat</NameOfSubstance>
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<CitationSubset>IM</CitationSubset>
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<MeshHeadingList><MeshHeading><DescriptorName UI="D000700" MajorTopicYN="N">Analgesics</DescriptorName>
<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
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<MeshHeading><DescriptorName UI="D020864" MajorTopicYN="N">Calcium Channels, N-Type</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D004594" MajorTopicYN="N">Electrophysiology</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D005470" MajorTopicYN="N">Fluorometry</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName>
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<MeshHeading><DescriptorName UI="D062550" MajorTopicYN="N">NAV1.1 Voltage-Gated Sodium Channel</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D062556" MajorTopicYN="N">NAV1.7 Voltage-Gated Sodium Channel</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D010455" MajorTopicYN="N">Peptides</DescriptorName>
<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D051381" MajorTopicYN="N">Rats</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D013111" MajorTopicYN="N">Spider Venoms</DescriptorName>
<QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D013112" MajorTopicYN="N">Spiders</DescriptorName>
<QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName>
</MeshHeading>
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Discovery and mode of action of a novel analgesic β-toxin from the African spider Ceratogyrus darlingi.

Discovery and mode of action of a novel analgesic β-toxin from the African spider Ceratogyrus darlingi.

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