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.
???displayArticle.abstract???
Although acetylcholine is widely utilized in vertebrate nervous systems, nicotinic acetylcholine receptors (nAChRs), including the α9α10 subtype, also are expressed in a wide variety of non-neuronal cells. These cell types include cochlear hair cells, adrenal chromaffin cells and immune cells. α9α10 nAChRs present in these cells may respectively play roles in protection from noise-induced hearing loss, response to stress and neuroprotection. Despite these critical functions, there are few available selective ligands to confirm mechanistic hypothesis regarding the role of α9α10 nAChRs. Conus, has been a rich source of ligands for receptors and ion channels. Here, we identified Conus geographus venom as a lead source for a novel α9α10 antagonist. The active component was isolated and the encoding gene cloned. The peptide signal sequence and cysteine arrangement had the signature of the σ-conotoxin superfamily. Previously isolated σ-conotoxin GVIIIA, also from Conus geographus, targets the 5-HT3 receptor. In contrast, αS-GVIIIB blocked the α9α10 nAChR with an IC50 of 9.8 nM, yet was inactive at the 5-HT3 receptor. Pharmacological characterization of αS-GVIIIB shows that it is over 100-fold selective for the α9α10 nAChR compared to other nAChR subtypes. Thus, the S-superfamily represents a novel conotoxin scaffold for flexibly targeting a variety of receptor subtypes. Functional competition studies utilized distinct off-rate kinetics of conotoxins to identify the α10/α9 nAChR interface as the site of αS-GVIIIB binding; this adds to the importance of the (+) face of the α10 rather than the (+) face of the α9 nAChR subunit as critical to binding of α9α10-targeted conotoxins.
Armishaw,
Conotoxins as research tools and drug leads.
2005, Pubmed
Armishaw,
Conotoxins as research tools and drug leads.
2005,
Pubmed
Azam,
Alpha-conotoxins as pharmacological probes of nicotinic acetylcholine receptors.
2009,
Pubmed
Azam,
Molecular basis for the differential sensitivity of rat and human α9α10 nAChRs to α-conotoxin RgIA.
2012,
Pubmed
,
Xenbase
Azam,
Molecular interaction of α-conotoxin RgIA with the rat α9α10 nicotinic acetylcholine receptor.
2015,
Pubmed
Barnes,
The 5-HT3 receptor--the relationship between structure and function.
2009,
Pubmed
Cartier,
A new alpha-conotoxin which targets alpha3beta2 nicotinic acetylcholine receptors.
1996,
Pubmed
,
Xenbase
Colomer,
Functional characterization of alpha9-containing cholinergic nicotinic receptors in the rat adrenal medulla: implication in stress-induced functional plasticity.
2010,
Pubmed
Di Cesare Mannelli,
α-conotoxin RgIA protects against the development of nerve injury-induced chronic pain and prevents both neuronal and glial derangement.
2014,
Pubmed
Dutertre,
Evolution of separate predation- and defence-evoked venoms in carnivorous cone snails.
2014,
Pubmed
Elgoyhen,
The nicotinic receptor of cochlear hair cells: a possible pharmacotherapeutic target?
2009,
Pubmed
Elgoyhen,
Alpha 9: an acetylcholine receptor with novel pharmacological properties expressed in rat cochlear hair cells.
1994,
Pubmed
,
Xenbase
Ellison,
Alpha-RgIA: a novel conotoxin that specifically and potently blocks the alpha9alpha10 nAChR.
2006,
Pubmed
,
Xenbase
England,
Inactivation of a serotonin-gated ion channel by a polypeptide toxin from marine snails.
1998,
Pubmed
Gotti,
Neuronal nicotinic receptors: from structure to pathology.
2004,
Pubmed
Gray,
Disulfide structures of highly bridged peptides: a new strategy for analysis.
1993,
Pubmed
Halai,
Scanning mutagenesis of alpha-conotoxin Vc1.1 reveals residues crucial for activity at the alpha9alpha10 nicotinic acetylcholine receptor.
2009,
Pubmed
,
Xenbase
Hu,
Elucidation of the molecular envenomation strategy of the cone snail Conus geographus through transcriptome sequencing of its venom duct.
2012,
Pubmed
Indurthi,
Presence of multiple binding sites on α9α10 nAChR receptors alludes to stoichiometric-dependent action of the α-conotoxin, Vc1.1.
2014,
Pubmed
,
Xenbase
Kaas,
ConoServer: updated content, knowledge, and discovery tools in the conopeptide database.
2012,
Pubmed
Kaas,
ConoServer, a database for conopeptide sequences and structures.
2008,
Pubmed
Kasheverov,
Design of new α-conotoxins: from computer modeling to synthesis of potent cholinergic compounds.
2011,
Pubmed
Kasheverov,
Naturally occurring and synthetic peptides acting on nicotinic acetylcholine receptors.
2009,
Pubmed
Kauferstein,
New conopeptides of the D-superfamily selectively inhibiting neuronal nicotinic acetylcholine receptors.
2009,
Pubmed
,
Xenbase
Kesters,
Structural basis of ligand recognition in 5-HT3 receptors.
2013,
Pubmed
Lebbe,
Conotoxins targeting nicotinic acetylcholine receptors: an overview.
2014,
Pubmed
Lebbe,
Discovery of a new subclass of α-conotoxins in the venom of Conus australis.
2014,
Pubmed
Lebbe,
Structure-function elucidation of a new α-conotoxin, Lo1a, from Conus longurionis.
2014,
Pubmed
,
Xenbase
Lee,
Overexpression and activation of the alpha9-nicotinic receptor during tumorigenesis in human breast epithelial cells.
2010,
Pubmed
Le Novère,
The diversity of subunit composition in nAChRs: evolutionary origins, physiologic and pharmacologic consequences.
2002,
Pubmed
Lipovsek,
Phylogenetic differences in calcium permeability of the auditory hair cell cholinergic nicotinic receptor.
2012,
Pubmed
,
Xenbase
Liu,
Identification of a novel S-superfamily conotoxin from vermivorous Conus caracteristicus.
2008,
Pubmed
Luo,
A novel inhibitor of α9α10 nicotinic acetylcholine receptors from Conus vexillum delineates a new conotoxin superfamily.
2013,
Pubmed
Maricq,
Primary structure and functional expression of the 5HT3 receptor, a serotonin-gated ion channel.
1991,
Pubmed
,
Xenbase
McIntosh,
Alpha9 nicotinic acetylcholine receptors and the treatment of pain.
2009,
Pubmed
,
Xenbase
Morales-González,
Diversity of A-conotoxins of three worm-hunting cone snails (Conus brunneus, Conus nux, and Conus princeps) from the Mexican Pacific coast.
2015,
Pubmed
Nguyen,
Isolation, purification and functional characterization of alpha-BnIA from Conus bandanus venom.
2014,
Pubmed
Olivera,
Conus peptides: biodiversity-based discovery and exogenomics.
2006,
Pubmed
Olivera,
Subtype-selective conopeptides targeted to nicotinic receptors: Concerted discovery and biomedical applications.
2008,
Pubmed
Peng,
A new subfamily of conotoxins belonging to the A-superfamily.
2010,
Pubmed
,
Xenbase
Puillandre,
Molecular phylogeny and evolution of the cone snails (Gastropoda, Conoidea).
2014,
Pubmed
Ren,
Pharmacological characterization of conotoxin lt14a as a potent non-addictive analgesic.
2015,
Pubmed
Simard,
Differential modulation of EAE by α9*- and β2*-nicotinic acetylcholine receptors.
2013,
Pubmed
Solt,
Differential effects of serotonin and dopamine on human 5-HT3A receptor kinetics: interpretation within an allosteric kinetic model.
2007,
Pubmed
Teichert,
Alpha S-conotoxin RVIIIA: a structurally unique conotoxin that broadly targets nicotinic acetylcholine receptors.
2005,
Pubmed
,
Xenbase
Terlau,
Conus venoms: a rich source of novel ion channel-targeted peptides.
2004,
Pubmed
Thompson,
5-HT3 receptors.
2006,
Pubmed
Vincler,
Molecular mechanism for analgesia involving specific antagonism of alpha9alpha10 nicotinic acetylcholine receptors.
2006,
Pubmed
Wang,
Characterization of a T-superfamily conotoxin TxVC from Conus textile that selectively targets neuronal nAChR subtypes.
2014,
Pubmed
,
Xenbase
Weisstaub,
The alpha9alpha10 nicotinic acetylcholine receptor is permeable to and is modulated by divalent cations.
2002,
Pubmed
,
Xenbase
Yu,
Determination of the α-conotoxin Vc1.1 binding site on the α9α10 nicotinic acetylcholine receptor.
2013,
Pubmed
Zouridakis,
Crystal structures of free and antagonist-bound states of human α9 nicotinic receptor extracellular domain.
2014,
Pubmed
,
Xenbase
