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.
Toxins (Basel)
2021 Aug 10;138:. doi: 10.3390/toxins13080555.
Show Gene links
Show Anatomy links
The Allosteric Activation of α7 nAChR by α-Conotoxin MrIC Is Modified by Mutations at the Vestibular Site.
Gulsevin A
,
Papke RL
,
Stokes C
,
Tran HNT
,
Jin AH
,
Vetter I
,
Meiler J
.
???displayArticle.abstract???
α-conotoxins are 13-19 amino acid toxin peptides that bind various nicotinic acetylcholine receptor (nAChR) subtypes. α-conotoxin Mr1.7c (MrIC) is a 17 amino acid peptide that targets α7 nAChR. Although MrIC has no activating effect on α7 nAChR when applied by itself, it evokes a large response when co-applied with the type II positive allosteric modulator PNU-120596, which potentiates the α7 nAChR response by recovering it from a desensitized state. A lack of standalone activity, despite activation upon co-application with a positive allosteric modulator, was previously observed for molecules that bind to an extracellular domain allosteric activation (AA) site at the vestibule of the receptor. We hypothesized that MrIC may activate α7 nAChR allosterically through this site. We ran voltage-clamp electrophysiology experiments and in silico peptide docking calculations in order to gather evidence in support of α7 nAChR activation by MrIC through the AA site. The experiments with the wild-type α7 nAChR supported an allosteric mode of action, which was confirmed by the significantly increased MrIC + PNU-120596 responses of three α7 nAChR AA site mutants that were designed in silico to improve MrIC binding. Overall, our results shed light on the allosteric activation of α7 nAChR by MrIC and suggest the involvement of the AA site.
Albuquerque,
Mammalian nicotinic acetylcholine receptors: from structure to function.
2009, Pubmed
Albuquerque,
Mammalian nicotinic acetylcholine receptors: from structure to function.
2009,
Pubmed
Alford,
The Rosetta All-Atom Energy Function for Macromolecular Modeling and Design.
2017,
Pubmed
Bagdas,
New Insights on Neuronal Nicotinic Acetylcholine Receptors as Targets for Pain and Inflammation: A Focus on α7 nAChRs.
2018,
Pubmed
Beinat,
The therapeutic potential of α7 nicotinic acetylcholine receptor (α7 nAChR) agonists for the treatment of the cognitive deficits associated with schizophrenia.
2015,
Pubmed
Bertrand,
The wonderland of neuronal nicotinic acetylcholine receptors.
2018,
Pubmed
Chi,
Solution conformation of a neuronal nicotinic acetylcholine receptor antagonist alpha-conotoxin OmIA that discriminates alpha3 vs. alpha6 nAChR subtypes.
2006,
Pubmed
Couturier,
A neuronal nicotinic acetylcholine receptor subunit (alpha 7) is developmentally regulated and forms a homo-oligomeric channel blocked by alpha-BTX.
1990,
Pubmed
,
Xenbase
Erak,
Peptide chemistry toolbox - Transforming natural peptides into peptide therapeutics.
2018,
Pubmed
Gill,
A series of α7 nicotinic acetylcholine receptor allosteric modulators with close chemical similarity but diverse pharmacological properties.
2012,
Pubmed
,
Xenbase
Gill,
Agonist activation of alpha7 nicotinic acetylcholine receptors via an allosteric transmembrane site.
2011,
Pubmed
,
Xenbase
Giribaldi,
α-Conotoxins to explore the molecular, physiological and pathophysiological functions of neuronal nicotinic acetylcholine receptors.
2018,
Pubmed
Gulsevin,
Allosteric Agonism of α7 Nicotinic Acetylcholine Receptors: Receptor Modulation Outside the Orthosteric Site.
2019,
Pubmed
,
Xenbase
Gulsevin,
Nicotinic receptor pharmacology in silico: Insights and challenges.
2020,
Pubmed
Gulsevin,
An Investigation of Three-Finger Toxin-nAChR Interactions through Rosetta Protein Docking.
2020,
Pubmed
Halevi,
Conservation within the RIC-3 gene family. Effectors of mammalian nicotinic acetylcholine receptor expression.
2003,
Pubmed
,
Xenbase
Horenstein,
Anti-inflammatory Silent Agonists.
2017,
Pubmed
Horenstein,
Critical Molecular Determinants of α7 Nicotinic Acetylcholine Receptor Allosteric Activation: SEPARATION OF DIRECT ALLOSTERIC ACTIVATION AND POSITIVE ALLOSTERIC MODULATION.
2016,
Pubmed
,
Xenbase
Hurst,
A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization.
2005,
Pubmed
,
Xenbase
Jin,
MrIC, a novel α-conotoxin agonist in the presence of PNU at endogenous α7 nicotinic acetylcholine receptors.
2014,
Pubmed
Jin,
Conotoxin Φ-MiXXVIIA from the Superfamily G2 Employs a Novel Cysteine Framework that Mimics Granulin and Displays Anti-Apoptotic Activity.
2017,
Pubmed
Kulkarni,
Microwave-assisted Expeditious and Efficient Synthesis of Cyclopentene Ring-fused Tetrahydroquinoline Derivatives Using Three-component Povarov Reaction.
2013,
Pubmed
Leaver-Fay,
Scientific benchmarks for guiding macromolecular energy function improvement.
2013,
Pubmed
Leffler,
Discovery of peptide ligands through docking and virtual screening at nicotinic acetylcholine receptor homology models.
2017,
Pubmed
Li,
Ligand-binding domain of an α7-nicotinic receptor chimera and its complex with agonist.
2011,
Pubmed
Liu,
Diversity and evolution of conotoxins in Conus virgo, Conus eburneus, Conus imperialis and Conus marmoreus from the South China Sea.
2012,
Pubmed
Martin,
Schizophrenia and the alpha7 nicotinic acetylcholine receptor.
2007,
Pubmed
Mineur,
Hippocampal α7 nicotinic ACh receptors contribute to modulation of depression-like behaviour in C57BL/6J mice.
2018,
Pubmed
Mueller,
α-Conotoxin MrIC is a biased agonist at α7 nicotinic acetylcholine receptors.
2015,
Pubmed
Palma,
Neuronal nicotinic alpha 7 receptor expressed in Xenopus oocytes presents five putative binding sites for methyllycaconitine.
1996,
Pubmed
,
Xenbase
Papke,
Differing Activity Profiles of the Stereoisomers of 2,3,5,6TMP-TQS, a Putative Silent Allosteric Modulator of α7 nAChR.
2020,
Pubmed
Papke,
Comparative pharmacology of rat and human alpha7 nAChR conducted with net charge analysis.
2002,
Pubmed
,
Xenbase
Papke,
Cysteine accessibility analysis of the human alpha7 nicotinic acetylcholine receptor ligand-binding domain identifies L119 as a gatekeeper.
2011,
Pubmed
,
Xenbase
Papke,
Working with OpusXpress: methods for high volume oocyte experiments.
2010,
Pubmed
,
Xenbase
Park,
Simultaneous Optimization of Biomolecular Energy Functions on Features from Small Molecules and Macromolecules.
2016,
Pubmed
Pettersen,
UCSF Chimera--a visualization system for exploratory research and analysis.
2004,
Pubmed
Prashanth,
Cone snail venomics: from novel biology to novel therapeutics.
2014,
Pubmed
Quadri,
Macroscopic and Microscopic Activation of α7 Nicotinic Acetylcholine Receptors by the Structurally Unrelated Allosteric Agonist-Positive Allosteric Modulators (ago-PAMs) B-973B and GAT107.
2019,
Pubmed
,
Xenbase
Raveh,
Sub-angstrom modeling of complexes between flexible peptides and globular proteins.
2010,
Pubmed
Santos,
The A-superfamily of conotoxins: structural and functional divergence.
2004,
Pubmed
Spurny,
Molecular blueprint of allosteric binding sites in a homologue of the agonist-binding domain of the α7 nicotinic acetylcholine receptor.
2015,
Pubmed
,
Xenbase
Stokes,
Heteromeric Neuronal Nicotinic Acetylcholine Receptors with Mutant β Subunits Acquire Sensitivity to α7-Selective Positive Allosteric Modulators.
2019,
Pubmed
,
Xenbase
Séguéla,
Molecular cloning, functional properties, and distribution of rat brain alpha 7: a nicotinic cation channel highly permeable to calcium.
1993,
Pubmed
,
Xenbase
Thakur,
Expeditious synthesis, enantiomeric resolution, and enantiomer functional characterization of (4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide (4BP-TQS): an allosteric agonist-positive allosteric modulator of α7 nicotinic acetylcholine receptors.
2013,
Pubmed
,
Xenbase
Tyka,
Alternate states of proteins revealed by detailed energy landscape mapping.
2011,
Pubmed
Ulens,
Structural determinants of selective alpha-conotoxin binding to a nicotinic acetylcholine receptor homolog AChBP.
2006,
Pubmed
Wallace,
Drug targets for cognitive enhancement in neuropsychiatric disorders.
2011,
Pubmed
Williams,
Investigation of the molecular mechanism of the α7 nicotinic acetylcholine receptor positive allosteric modulator PNU-120596 provides evidence for two distinct desensitized states.
2011,
Pubmed
,
Xenbase
Williams,
The effective opening of nicotinic acetylcholine receptors with single agonist binding sites.
2011,
Pubmed
,
Xenbase
Yu,
Blockade of neuronal α7-nAChR by α-conotoxin ImI explained by computational scanning and energy calculations.
2011,
Pubmed
Zhao,
Pharmacologic activation of cholinergic alpha7 nicotinic receptors mitigates depressive-like behavior in a mouse model of chronic stress.
2017,
Pubmed