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.
Mol Pharmacol
2009 Aug 01;762:253-63. doi: 10.1124/mol.109.056226.
Show Gene links
Show Anatomy links
An allosteric modulator of alpha7 nicotinic receptors, N-(5-Chloro-2,4-dimethoxyphenyl)-N'-(5-methyl-3-isoxazolyl)-urea (PNU-120596), causes conformational changes in the extracellular ligand binding domain similar to those caused by acetylcholine.
Barron SC, McLaughlin JT, See JA, Richards VL, Rosenberg RL.
???displayArticle.abstract???
Nicotinic acetylcholine receptors are implicated in several neuropsychiatric disorders, including nicotine addiction, Alzheimer's, schizophrenia, and depression. Therefore, they represent a critical molecular target for drug development and targeted therapeutic intervention. Understanding the molecular mechanisms by which allosteric modulators enhance activation of these receptors is crucial to the development of new drugs. We used the substituted cysteine accessibility method to study conformational changes induced by the positive allosteric modulator N-(5-chloro-2,4-dimethoxyphenyl)-N'-(5-methyl-3-isoxazolyl)-urea (PNU-120596) in the extracellular ligand binding domain of alpha7 nicotinic receptors carrying the L247T mutation. PNU-120596 caused changes in cysteine accessibility at the inner beta sheet, transition zone, and agonist binding site. These changes in accessibility are similar to but not identical to those caused by ACh alone. In particular, PNU-120596 induced changes in MTSEA accessibility at N170C (in the transition zone) that were substantially different from those evoked by acetylcholine (ACh). We found that PNU-120596 induced changes at position E172C in the absence of allosteric modulation. We identified a cysteine mutation of the agonist binding site (W148C) that exhibited an unexpected phenotype in which PNU-120596 acts as a full agonist. In this mutant, ACh-evoked currents were more sensitive to thiol modification than PNU-evoked currents, suggesting that PNU-120596 does not bind at unoccupied agonist-binding sites. Our results provide evidence that binding sites for PNU-120596 are not in the agonist-binding sites and demonstrate that positive allosteric modulators such as PNU-120596 enhance agonist-evoked gating of nicotinic receptors by eliciting conformational effects that are similar but nonidentical to the gating conformations promoted by ACh.
Akabas,
Acetylcholine receptor channel structure probed in cysteine-substitution mutants.
1992,
Pubmed
,
Xenbase Amin,
Two tyrosine residues on the alpha subunit are crucial for benzodiazepine binding and allosteric modulation of gamma-aminobutyric acidA receptors.
1997,
Pubmed
,
Xenbase Bertrand,
Allosteric modulation of nicotinic acetylcholine receptors.
2007,
Pubmed Bertrand,
Positive allosteric modulation of the alpha7 nicotinic acetylcholine receptor: ligand interactions with distinct binding sites and evidence for a prominent role of the M2-M3 segment.
2008,
Pubmed
,
Xenbase Bianchi,
Mutation of the 9' leucine in the GABA(A) receptor gamma2L subunit produces an apparent decrease in desensitization by stabilizing open states without altering desensitized states.
2001,
Pubmed Bouzat,
Coupling of agonist binding to channel gating in an ACh-binding protein linked to an ion channel.
2004,
Pubmed Brejc,
Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors.
2001,
Pubmed Celie,
Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures.
2004,
Pubmed Chang,
Site-specific fluorescence reveals distinct structural changes with GABA receptor activation and antagonism.
2002,
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 Filatov,
The role of conserved leucines in the M2 domain of the acetylcholine receptor in channel gating.
1995,
Pubmed
,
Xenbase Galzi,
Identification of calcium binding sites that regulate potentiation of a neuronal nicotinic acetylcholine receptor.
1996,
Pubmed
,
Xenbase Gay,
Gating of nicotinic ACh receptors; new insights into structural transitions triggered by agonist binding that induce channel opening.
2007,
Pubmed Gay,
Aromatic residues at position 55 of rat alpha7 nicotinic acetylcholine receptors are critical for maintaining rapid desensitization.
2008,
Pubmed
,
Xenbase Gotti,
Neuronal nicotinic receptors: from structure to pathology.
2004,
Pubmed Grønlien,
Distinct profiles of alpha7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes.
2007,
Pubmed
,
Xenbase Günther,
Benzodiazepine-insensitive mice generated by targeted disruption of the gamma 2 subunit gene of gamma-aminobutyric acid type A receptors.
1995,
Pubmed Hansen,
Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations.
2005,
Pubmed Hurst,
A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization.
2005,
Pubmed
,
Xenbase Jackson,
Perfection of a synaptic receptor: kinetics and energetics of the acetylcholine receptor.
1989,
Pubmed Karlin,
Emerging structure of the nicotinic acetylcholine receptors.
2002,
Pubmed Lansdell,
RIC-3 enhances functional expression of multiple nicotinic acetylcholine receptor subtypes in mammalian cells.
2005,
Pubmed
,
Xenbase Lyford,
Agonist-induced conformational changes in the extracellular domain of alpha 7 nicotinic acetylcholine receptors.
2003,
Pubmed
,
Xenbase McLaughlin,
Role of the outer beta-sheet in divalent cation modulation of alpha7 nicotinic receptors.
2006,
Pubmed
,
Xenbase McLaughlin,
Agonist-driven conformational changes in the inner beta-sheet of alpha7 nicotinic receptors.
2007,
Pubmed
,
Xenbase McLaughlin,
Conformational changes in alpha 7 acetylcholine receptors underlying allosteric modulation by divalent cations.
2009,
Pubmed
,
Xenbase Mihalak,
Varenicline is a partial agonist at alpha4beta2 and a full agonist at alpha7 neuronal nicotinic receptors.
2006,
Pubmed
,
Xenbase Orr-Urtreger,
Mice deficient in the alpha7 neuronal nicotinic acetylcholine receptor lack alpha-bungarotoxin binding sites and hippocampal fast nicotinic currents.
1997,
Pubmed Pascual,
State-dependent accessibility and electrostatic potential in the channel of the acetylcholine receptor. Inferences from rates of reaction of thiosulfonates with substituted cysteines in the M2 segment of the alpha subunit.
1998,
Pubmed
,
Xenbase Pless,
Conformational variability of the glycine receptor M2 domain in response to activation by different agonists.
2007,
Pubmed
,
Xenbase Purohit,
Unliganded gating of acetylcholine receptor channels.
2009,
Pubmed Revah,
Mutations in the channel domain alter desensitization of a neuronal nicotinic receptor.
1991,
Pubmed
,
Xenbase Sharkey,
Individually monitoring ligand-induced changes in the structure of the GABAA receptor at benzodiazepine binding site and non-binding-site interfaces.
2008,
Pubmed
,
Xenbase 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 Venkatachalan,
A conserved salt bridge critical for GABA(A) receptor function and loop C dynamics.
2008,
Pubmed
,
Xenbase Xiu,
A unified view of the role of electrostatic interactions in modulating the gating of Cys loop receptors.
2005,
Pubmed
,
Xenbase Young,
Potentiation of alpha7 nicotinic acetylcholine receptors via an allosteric transmembrane site.
2008,
Pubmed
,
Xenbase Zhang,
Agonist- and antagonist-induced conformational changes of loop F and their contributions to the rho1 GABA receptor function.
2009,
Pubmed
,
Xenbase Zhong,
From ab initio quantum mechanics to molecular neurobiology: a cation-pi binding site in the nicotinic receptor.
1998,
Pubmed
