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.
The positive allosteric modulator morantel binds at noncanonical subunit interfaces of neuronal nicotinic acetylcholine receptors.
Seo S
,
Henry JT
,
Lewis AH
,
Wang N
,
Levandoski MM
.
???displayArticle.abstract???
We are interested in the positive allosteric modulation of neuronal nicotinic acetylcholine (ACh) receptors and have recently shown that the anthelmintic compound morantel potentiates by enhancing channel gating of the alpha3beta2 subtype. Based on the demonstration that morantel-elicited currents were inhibited by the classic ACh competitor dihydro-beta-erythroidine in a noncompetitive manner and that morantel still potentiates at saturating concentrations of agonist (Wu et al., 2008), we hypothesized that morantel binds at the noncanonical beta2(+)/alpha3(-) subunit interface. In the present study, we created seven cysteine-substituted subunits by site-directed mutagenesis, choosing residues in the putative morantel binding site with the aid of structural homology models. We coexpressed the mutant subunits and their respective wild-type partners in Xenopus oocytes and characterized the morantel potentiation of ACh-evoked currents, as well as morantel-evoked currents, before and after treatment with a variety of methanethiosulfonate (MTS)-based compounds, using voltage-clamp recordings. The properties of four of the seven mutants, two residues on each side of the interface, were changed by MTS treatments. Coapplication with ACh enhanced the extent of MTS modification for alpha3A106Cbeta2 and alpha3beta2S192C receptors. The activities of two mutants, alpha3T115Cbeta2 and alpha3beta2T150C, were dramatically altered by MTS modification. For alpha3beta2T150C, while peak current amplitudes were reduced, potentiation was enhanced. For alpha3T115Cbeta2, both current amplitudes and potentiation were reduced. MTS modification and morantel were mutually inhibitory: MTS treatment decreased morantel-evoked currents and morantel decreased the rate of MTS modification. We conclude that the four residues showing MTS effects contribute to the morantel binding site.
Akk,
Galantamine activates muscle-type nicotinic acetylcholine receptors without binding to the acetylcholine-binding site.
2005, Pubmed
Akk,
Galantamine activates muscle-type nicotinic acetylcholine receptors without binding to the acetylcholine-binding site.
2005,
Pubmed
Arias,
Molecular mechanisms and binding site location for the noncompetitive antagonist crystal violet on nicotinic acetylcholine receptors.
2006,
Pubmed
Arias,
Localization of agonist and competitive antagonist binding sites on nicotinic acetylcholine receptors.
2000,
Pubmed
Bertrand,
Allosteric modulation of nicotinic acetylcholine receptors.
2007,
Pubmed
Birks,
Cholinesterase inhibitors for Alzheimer's disease.
2006,
Pubmed
Brejc,
Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors.
2001,
Pubmed
Buhr,
A point mutation in the gamma2 subunit of gamma-aminobutyric acid type A receptors results in altered benzodiazepine binding site specificity.
1997,
Pubmed
,
Xenbase
Celie,
Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures.
2004,
Pubmed
Chavez-Noriega,
Pharmacological characterization of recombinant human neuronal nicotinic acetylcholine receptors h alpha 2 beta 2, h alpha 2 beta 4, h alpha 3 beta 2, h alpha 3 beta 4, h alpha 4 beta 2, h alpha 4 beta 4 and h alpha 7 expressed in Xenopus oocytes.
1997,
Pubmed
,
Xenbase
Chiara,
Structure of the agonist-binding sites of the Torpedo nicotinic acetylcholine receptor: affinity-labeling and mutational analyses identify gamma Tyr-111/delta Arg-113 as antagonist affinity determinants.
1999,
Pubmed
,
Xenbase
Cohen,
Regions of beta 2 and beta 4 responsible for differences between the steady state dose-response relationships of the alpha 3 beta 2 and alpha 3 beta 4 neuronal nicotinic receptors.
1995,
Pubmed
,
Xenbase
Colquhoun,
Binding, gating, affinity and efficacy: the interpretation of structure-activity relationships for agonists and of the effects of mutating receptors.
1998,
Pubmed
Curtis,
Potentiation of human alpha4beta2 neuronal nicotinic acetylcholine receptor by estradiol.
2002,
Pubmed
,
Xenbase
Hansen,
Galanthamine and non-competitive inhibitor binding to ACh-binding protein: evidence for a binding site on non-alpha-subunit interfaces of heteromeric neuronal nicotinic receptors.
2007,
Pubmed
Harvey,
Determinants of competitive antagonist sensitivity on neuronal nicotinic receptor beta subunits.
1996,
Pubmed
,
Xenbase
Hogg,
Partial agonists as therapeutic agents at neuronal nicotinic acetylcholine receptors.
2007,
Pubmed
Hsiao,
Determinants of zinc potentiation on the alpha4 subunit of neuronal nicotinic receptors.
2006,
Pubmed
,
Xenbase
Hsiao,
Zinc potentiates neuronal nicotinic receptors by increasing burst duration.
2008,
Pubmed
,
Xenbase
Hurst,
A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization.
2005,
Pubmed
,
Xenbase
Jensen,
Neuronal nicotinic acetylcholine receptors: structural revelations, target identifications, and therapeutic inspirations.
2005,
Pubmed
Karlin,
Substituted-cysteine accessibility method.
1998,
Pubmed
Karlin,
Emerging structure of the nicotinic acetylcholine receptors.
2002,
Pubmed
Lee,
Invariant aspartic Acid in muscle nicotinic receptor contributes selectively to the kinetics of agonist binding.
2004,
Pubmed
Lee,
Principal pathway coupling agonist binding to channel gating in nicotinic receptors.
2005,
Pubmed
Levandoski,
The anthelmintic levamisole is an allosteric modulator of human neuronal nicotinic acetylcholine receptors.
2003,
Pubmed
,
Xenbase
Lyford,
Agonist-induced conformational changes in the extracellular domain of alpha 7 nicotinic acetylcholine receptors.
2003,
Pubmed
,
Xenbase
Maelicke,
Allosteric modulation of nicotinic acetylcholine receptors as a treatment strategy for Alzheimer's disease.
2000,
Pubmed
Martin,
Modes of action of anthelmintic drugs.
1997,
Pubmed
Moroni,
Non-agonist-binding subunit interfaces confer distinct functional signatures to the alternate stoichiometries of the alpha4beta2 nicotinic receptor: an alpha4-alpha4 interface is required for Zn2+ potentiation.
2008,
Pubmed
,
Xenbase
Nirthanan,
Identification of binding sites in the nicotinic acetylcholine receptor for TDBzl-etomidate, a photoreactive positive allosteric effector.
2008,
Pubmed
Palma,
Neuronal nicotinic alpha 7 receptor expressed in Xenopus oocytes presents five putative binding sites for methyllycaconitine.
1996,
Pubmed
,
Xenbase
Paterson,
Neuronal nicotinic receptors in the human brain.
2000,
Pubmed
,
Xenbase
Romanelli,
Cholinergic nicotinic receptors: competitive ligands, allosteric modulators, and their potential applications.
2003,
Pubmed
Sallette,
An extracellular protein microdomain controls up-regulation of neuronal nicotinic acetylcholine receptors by nicotine.
2004,
Pubmed
Sanders,
A novel pharmatope tag inserted into the beta4 subunit confers allosteric modulation to neuronal nicotinic receptors.
2004,
Pubmed
,
Xenbase
Sine,
The nicotinic receptor ligand binding domain.
2002,
Pubmed
Sine,
Lysine scanning mutagenesis delineates structural model of the nicotinic receptor ligand binding domain.
2002,
Pubmed
Siu,
Non-nicotinic therapies for smoking cessation.
2007,
Pubmed
Timmermann,
An allosteric modulator of the alpha7 nicotinic acetylcholine receptor possessing cognition-enhancing properties in vivo.
2007,
Pubmed
,
Xenbase
Unwin,
Refined structure of the nicotinic acetylcholine receptor at 4A resolution.
2005,
Pubmed
Wagner,
Structure and dynamics of the GABA binding pocket: A narrowing cleft that constricts during activation.
2001,
Pubmed
,
Xenbase
Wu,
Morantel allosterically enhances channel gating of neuronal nicotinic acetylcholine alpha 3 beta 2 receptors.
2008,
Pubmed
,
Xenbase
Zhong,
From ab initio quantum mechanics to molecular neurobiology: a cation-pi binding site in the nicotinic receptor.
1998,
Pubmed