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

卷:127

Article

Zhangsun, Dongting¹  Zhu, Xiaopeng¹  Kaas, Quentin²  Wu, Yong¹  Craik, David J.²  McIntosh, J. Michael^3,4  Luo, Sulan¹ 

[1] Hainan Univ, Minist Educ, Key Lab Trop Biol Resources, Key Lab Marine Drug Haikou, Haikou 570228, Hainan, Peoples R China

[2] Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia

[3] Univ Utah, Dept Biol & Psychiat, Salt Lake City, UT 84112 USA

[4] Vet Affairs Med Ctr, George E Wahlen Dept, Salt Lake City, UT 84108 USA

关键词: alpha O-conotoxin GeXIVA disulfide bond isomers;    Human and rat nAChRs;    alpha 9 alpha 10 nAChR subtype and its mutants;    Differential sensitivity;    Mechanism of action;   

DOI  :  10.1016/j.neuropharm.2017.04.015

来源: Elsevier

【 摘 要 】

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 alpha 9 alpha 10 nAChR is a potential target in chronic pain, wound healing, the pathophysiology of the auditory system, and breast and lung cancers. alpha O-conotoxin GeXIVA is a potent antagonist of rat alpha 9 alpha 10 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 alpha 9 alpha 10 nAChRs, other human nAChR subtypes, various rat nAChR subtypes, and 10 rat alpha 9 alpha 10 nAChR mutants. The three isomers displayed only-5-fold difference in potency on the human vs rat alpha 9 alpha 10 receptors and had similar affinities at wild-type rat 0000 nAChRs and all 10 alpha 9 alpha 10 receptor mutants. From these findings, the binding site and mechanism of action of GeXIVA on rat and human alpha 9 alpha 10 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 alpha 9 alpha 10 nAChR. This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.' (C) 2017 Elsevier Ltd. All rights reserved.

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