αO-Conotoxin GeXIVA disulfide bond isomers exhibit differential sensitivity for various nicotinic acetylcholine receptors but retain potency and selectivity for the human α9α10 subtype

Zhangsun, Dongting, Zhu, Xiaopeng, Kaas, Quentin, Wu, Yong, Craik, David J. , McIntosh, J. Michael and Luo, Sulan (2017) αO-Conotoxin GeXIVA disulfide bond isomers exhibit differential sensitivity for various nicotinic acetylcholine receptors but retain potency and selectivity for the human α9α10 subtype. Neuropharmacology, . doi:10.1016/j.neuropharm.2017.04.015


Author Zhangsun, Dongting
Zhu, Xiaopeng
Kaas, Quentin
Wu, Yong
Craik, David J.
McIntosh, J. Michael
Luo, Sulan
Title αO-Conotoxin GeXIVA disulfide bond isomers exhibit differential sensitivity for various nicotinic acetylcholine receptors but retain potency and selectivity for the human α9α10 subtype
Journal name Neuropharmacology   Check publisher's open access policy
ISSN 1873-7064
Publication date 2017-04-14
Sub-type Article (original research)
DOI 10.1016/j.neuropharm.2017.04.015
Open Access Status Not yet assessed
Total pages 10
Place of publication Kidlington, Oxford, United Kingdom
Publisher Pergamon Press
Language eng
Abstract Nicotinic acetylcholine receptor (nAChR) subtypes exhibit distinct neuropharmacological properties that are involved in a range of neuropathological conditions, including pain, addiction, epilepsy, autism, schizophrenia, Tourette's syndrome, Alzheimer's and Parkinson's diseases, as well as many types of cancer. The α9α10 nAChR is a potential target in chronic pain, wound healing, the pathophysiology of the auditory system, and breast and lung cancers. αO-conotoxin GeXIVA is a potent antagonist of rat α9α10 nAChRs, with the 'bead' disulfide bond isomer displaying the lowest IC50 of the three possible isomers. In the rat chronic constriction injury model of neuropathic pain, this isomer reduced mechanical hyperalgesia without affecting motor performance. Here, we report the effects of the three disulfide bond isomers of GeXIVA on human α9α10 nAChRs, other human nAChR subtypes, various rat nAChR subtypes, and 10 rat α9α10 nAChR mutants. The three isomers displayed only ∼5-fold difference in potency on the human vs rat α9α10 receptors and had similar affinities at wild-type rat α9α10 nAChRs and all 10 α9α10 receptor mutants. From these findings, the binding site and mechanism of action of GeXIVA on rat and human α9α10 nAChR was deduced to be different from that of other conotoxins targeting this nAChR subtype. GeXIVA is therefore a unique ligand that might prove useful for further probing of binding sites on the α9α10 nAChR.
Keyword Differential sensitivity
Human and rat nAChRs
Mechanism of action
α9α10 nAChR subtype and its mutants
αO-conotoxin GeXIVA disulfide bond isomers
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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