α-Conotoxin VnIB from Conus ventricosus is a potent and selective antagonist of α6β4* nicotinic acetylcholine receptors.
Conus
Nicotinic acetylcholine receptor (nAChR)
α-Conotoxin (α-Ctx)
α-Ctx VnIB
α6-containing nAChRs
α6β4 nAChRs
Journal
Neuropharmacology
ISSN: 1873-7064
Titre abrégé: Neuropharmacology
Pays: England
ID NLM: 0236217
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
21
03
2019
revised:
05
06
2019
accepted:
26
06
2019
pubmed:
1
7
2019
medline:
22
7
2020
entrez:
1
7
2019
Statut:
ppublish
Résumé
α6-containing (α6*) nicotinic acetylcholine receptors (nAChRs) are expressed throughout the periphery and the central nervous system and constitute putative therapeutic targets in pain, addiction and movement disorders. The α6β2* nAChRs are relatively well studied, in part due to the availability of target specific α-conotoxins (α-Ctxs). In contrast, all native α-Ctxs identified that potently block α6β4 nAChRs exhibit higher potencies for the closely related α6β2β3 and/or α3β4 subtypes. In this study, we have identified a novel peptide from Conus ventricosus with pronounced selectivity for the α6β4 nAChR. The peptide-encoding gene was cloned from genomic DNA and the predicted mature peptide, α-Ctx VnIB, was synthesized. The functional properties of VnIB were characterized at rat and human nAChRs expressed in Xenopus oocytes by two-electrode voltage clamp electrophysiology. VnIB potently inhibited ACh-evoked currents at rα6β4 and rα6/α3β4 nAChRs, displayed ∼20-fold and ∼250-fold lower potencies at rα3β4 and rα6/α3β2β3 receptors, respectively, and exhibited negligible effects at eight other nAChR subtypes. Interestingly, even higher degrees of selectivity were observed for hα6/α3β4 over hα6/α3β2β3 and hα3β4 receptors. Finally, VnIB displayed fast binding kinetics at rα6/α3β4 (on-rate t
Identifiants
pubmed: 31255696
pii: S0028-3908(19)30247-3
doi: 10.1016/j.neuropharm.2019.107691
pmc: PMC6693646
mid: NIHMS1534582
pii:
doi:
Substances chimiques
Conotoxins
0
Nicotinic Antagonists
0
Receptors, Nicotinic
0
Acetylcholine
N9YNS0M02X
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
107691Subventions
Organisme : NIGMS NIH HHS
ID : P01 GM048677
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM103801
Pays : United States
Informations de copyright
Published by Elsevier Ltd.
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