Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Neuropharmacology
2017 Dec 01;127:243-252. doi: 10.1016/j.neuropharm.2017.04.015.
Show Gene links
Show Anatomy links
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 D
,
Zhu X
,
Kaas Q
,
Wu Y
,
Craik DJ
,
McIntosh JM
,
Luo S
.
???displayArticle.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. This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.'
Adams,
Mechanisms of conotoxin inhibition of N-type (Ca(v)2.2) calcium channels.
2013, Pubmed
Adams,
Mechanisms of conotoxin inhibition of N-type (Ca(v)2.2) calcium channels.
2013,
Pubmed
Armishaw,
Establishing regiocontrol of disulfide bond isomers of alpha-conotoxin ImI via the synthesis of N-to-C cyclic analogs.
2010,
Pubmed
Azam,
Molecular interaction of α-conotoxin RgIA with the rat α9α10 nicotinic acetylcholine receptor.
2015,
Pubmed
Azam,
Molecular basis for the differential sensitivity of rat and human α9α10 nAChRs to α-conotoxin RgIA.
2012,
Pubmed
,
Xenbase
Berecki,
Differential Cav2.1 and Cav2.3 channel inhibition by baclofen and α-conotoxin Vc1.1 via GABAB receptor activation.
2014,
Pubmed
Callaghan,
Analgesic α-conotoxins Vc1.1 and RgIA inhibit N-type calcium channels in sensory neurons of α9 nicotinic receptor knockout mice.
2010,
Pubmed
Callaghan,
Analgesic alpha-conotoxins Vc1.1 and Rg1A inhibit N-type calcium channels in rat sensory neurons via GABAB receptor activation.
2008,
Pubmed
,
Xenbase
Cartier,
A new alpha-conotoxin which targets alpha3beta2 nicotinic acetylcholine receptors.
1996,
Pubmed
,
Xenbase
Chen,
Nicotine-induced human breast cancer cell proliferation attenuated by garcinol through down-regulation of the nicotinic receptor and cyclin D3 proteins.
2011,
Pubmed
Chikova,
New associations of the genetic polymorphisms in nicotinic receptor genes with the risk of lung cancer.
2012,
Pubmed
Cuny,
γ-Aminobutyric acid type B (GABAB) receptor expression is needed for inhibition of N-type (Cav2.2) calcium channels by analgesic α-conotoxins.
2012,
Pubmed
Davis,
Remarkable inter- and intra-species complexity of conotoxins revealed by LC/MS.
2009,
Pubmed
Dowell,
Alpha-conotoxin PIA is selective for alpha6 subunit-containing nicotinic acetylcholine receptors.
2003,
Pubmed
,
Xenbase
Dutton,
A new level of conotoxin diversity, a non-native disulfide bond connectivity in alpha-conotoxin AuIB reduces structural definition but increases biological activity.
2002,
Pubmed
Gehrmann,
Structure determination of the three disulfide bond isomers of alpha-conotoxin GI: a model for the role of disulfide bonds in structural stability.
1998,
Pubmed
Grishin,
Alpha-conotoxin AuIB isomers exhibit distinct inhibitory mechanisms and differential sensitivity to stoichiometry of alpha3beta4 nicotinic acetylcholine receptors.
2010,
Pubmed
,
Xenbase
Halai,
Conotoxins: natural product drug leads.
2009,
Pubmed
Halai,
Scanning mutagenesis of alpha-conotoxin Vc1.1 reveals residues crucial for activity at the alpha9alpha10 nicotinic acetylcholine receptor.
2009,
Pubmed
,
Xenbase
Huynh,
Novel mechanism of voltage-gated N-type (Cav2.2) calcium channel inhibition revealed through α-conotoxin Vc1.1 activation of the GABA(B) receptor.
2015,
Pubmed
Kaas,
ConoServer: updated content, knowledge, and discovery tools in the conopeptide database.
2012,
Pubmed
Klimis,
A novel mechanism of inhibition of high-voltage activated calcium channels by α-conotoxins contributes to relief of nerve injury-induced neuropathic pain.
2011,
Pubmed
Lavergne,
Optimized deep-targeted proteotranscriptomic profiling reveals unexplored Conus toxin diversity and novel cysteine frameworks.
2015,
Pubmed
Lewis,
Conus venom peptide pharmacology.
2012,
Pubmed
Li,
Anti-hypersensitive effect of intramuscular administration of αO-conotoxin GeXIVA[1,2] and GeXIVA[1,4] in rats of neuropathic pain.
2016,
Pubmed
Lindorff-Larsen,
Improved side-chain torsion potentials for the Amber ff99SB protein force field.
2010,
Pubmed
Livett,
Therapeutic applications of conotoxins that target the neuronal nicotinic acetylcholine receptor.
2006,
Pubmed
Luo,
A novel inhibitor of α9α10 nicotinic acetylcholine receptors from Conus vexillum delineates a new conotoxin superfamily.
2013,
Pubmed
Luo,
Cloning, synthesis, and characterization of αO-conotoxin GeXIVA, a potent α9α10 nicotinic acetylcholine receptor antagonist.
2015,
Pubmed
,
Xenbase
McIntosh,
A novel alpha-conotoxin, PeIA, cloned from Conus pergrandis, discriminates between rat alpha9alpha10 and alpha7 nicotinic cholinergic receptors.
2005,
Pubmed
,
Xenbase
McIntosh,
Alpha9 nicotinic acetylcholine receptors and the treatment of pain.
2009,
Pubmed
,
Xenbase
Mohammadi,
Conotoxin Interactions with α9α10-nAChRs: Is the α9α10-Nicotinic Acetylcholine Receptor an Important Therapeutic Target for Pain Management?
2015,
Pubmed
Mohammadi,
α9-nicotinic acetylcholine receptors contribute to the maintenance of chronic mechanical hyperalgesia, but not thermal or mechanical allodynia.
2014,
Pubmed
Nevin,
Are alpha9alpha10 nicotinic acetylcholine receptors a pain target for alpha-conotoxins?
2007,
Pubmed
,
Xenbase
Puillandre,
One, four or 100 genera? A new classification of the cone snails.
2015,
Pubmed
Sali,
Comparative protein modelling by satisfaction of spatial restraints.
1993,
Pubmed
Satkunanathan,
Alpha-conotoxin Vc1.1 alleviates neuropathic pain and accelerates functional recovery of injured neurones.
2005,
Pubmed
Uribe,
Beyond Conus: Phylogenetic relationships of Conidae based on complete mitochondrial genomes.
2017,
Pubmed
Vincler,
Molecular mechanism for analgesia involving specific antagonism of alpha9alpha10 nicotinic acetylcholine receptors.
2006,
Pubmed
Walker,
The T-superfamily of conotoxins.
1999,
Pubmed
Wright,
Limited efficacy of α-conopeptides, Vc1.1 and RgIA, to inhibit sensory neuron CaV current.
2015,
Pubmed
Wu,
Nicotinic acetylcholine receptor-based blockade: applications of molecular targets for cancer therapy.
2011,
Pubmed
Xu,
Conotoxin αD-GeXXA utilizes a novel strategy to antagonize nicotinic acetylcholine receptors.
2015,
Pubmed
Yu,
Determination of the α-conotoxin Vc1.1 binding site on the α9α10 nicotinic acetylcholine receptor.
2013,
Pubmed
van Lierop,
Dicarba α-conotoxin Vc1.1 analogues with differential selectivity for nicotinic acetylcholine and GABAB receptors.
2013,
Pubmed
,
Xenbase
