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
2011 Dec 01;806:1013-32. doi: 10.1124/mol.111.074302.
Show Gene links
Show Anatomy links
Investigation of the molecular mechanism of the α7 nicotinic acetylcholine receptor positive allosteric modulator PNU-120596 provides evidence for two distinct desensitized states.
Williams DK
,
Wang J
,
Papke RL
.
???displayArticle.abstract???
Although α7 nicotinic acetylcholine receptors are considered potentially important therapeutic targets, the development of selective agonists has been stymied by the α7 receptor's intrinsically low probability of opening (P(open)) and the concern that an agonist-based therapeutic approach would disrupt endogenous cholinergic function. Development of α7 positive allosteric modulators (PAMs) holds promise of avoiding both issues. N-(5-Chloro-2,4-dimethoxyphenyl)-N'-(5-methyl-3-isoxazolyl)-urea (PNU-120596) is one of the most effective α7 PAMs, with a mechanism associated, at least in part, with the destabilization of desensitized states. We studied the mechanism of PNU-120596 potentiation of α7 receptors expressed in Xenopus laevis oocytes and outside-out patches from BOSC 23 cells. We identify two forms of α7 desensitization: one is destabilized by PNU-120596 (D(s)), and the other is induced by strong episodes of activation and is stable in the presence of the PAM (D(i)). Our characterization of prolonged bursts of single-channel currents that occur with PNU-120596 provide a remarkable contrast to the behavior of the channels in the absence of the PAM. Individual channels that avoid the D(i) state show a 100,000-fold increase in P(open) compared with receptors in the nonpotentiated state. In the presence of PNU-120596, balance between D(s) and D(i) is dynamically regulated by both agonist and PAM binding, with maximal ion channel activity at intermediate levels of binding to both classes of sites. In the presence of high agonist concentrations, competitive antagonists may have the effect of shifting the balance in favor of D(s) and increasing ion channel currents.
Bertrand,
Paradoxical allosteric effects of competitive inhibitors on neuronal alpha7 nicotinic receptor mutants.
1997, Pubmed,
Xenbase
Bertrand,
Paradoxical allosteric effects of competitive inhibitors on neuronal alpha7 nicotinic receptor mutants.
1997,
Pubmed
,
Xenbase
Bouzat,
The interface between extracellular and transmembrane domains of homomeric Cys-loop receptors governs open-channel lifetime and rate of desensitization.
2008,
Pubmed
Colquhoun,
Fast events in single-channel currents activated by acetylcholine and its analogues at the frog muscle end-plate.
1985,
Pubmed
Dinklo,
Characterization of 2-[[4-fluoro-3-(trifluoromethyl)phenyl]amino]-4-(4-pyridinyl)-5-thiazolemethanol (JNJ-1930942), a novel positive allosteric modulator of the {alpha}7 nicotinic acetylcholine receptor.
2011,
Pubmed
Dunlop,
Old and new pharmacology: positive allosteric modulation of the alpha7 nicotinic acetylcholine receptor by the 5-hydroxytryptamine(2B/C) receptor antagonist SB-206553 (3,5-dihydro-5-methyl-N-3-pyridinylbenzo[1,2-b:4,5-b']di pyrrole-1(2H)-carboxamide).
2009,
Pubmed
Gopalakrishnan,
Functional characterization and high-throughput screening of positive allosteric modulators of α7 nicotinic acetylcholine receptors in IMR-32 neuroblastoma cells.
2011,
Pubmed
,
Xenbase
Grønlien,
Distinct profiles of alpha7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes.
2007,
Pubmed
,
Xenbase
Halevi,
The C. elegans ric-3 gene is required for maturation of nicotinic acetylcholine receptors.
2002,
Pubmed
,
Xenbase
Heidmann,
Structural and functional properties of the acetylcholine receptor protein in its purified and membrane-bound states.
1978,
Pubmed
Hibbs,
Structural determinants for interaction of partial agonists with acetylcholine binding protein and neuronal alpha7 nicotinic acetylcholine receptor.
2009,
Pubmed
Horenstein,
Reversal of agonist selectivity by mutations of conserved amino acids in the binding site of nicotinic acetylcholine receptors.
2007,
Pubmed
,
Xenbase
Hu,
Positive allosteric modulation of alpha7 neuronal nicotinic acetylcholine receptors: lack of cytotoxicity in PC12 cells and rat primary cortical neurons.
2009,
Pubmed
Hurst,
A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization.
2005,
Pubmed
,
Xenbase
Lape,
On the nature of partial agonism in the nicotinic receptor superfamily.
2008,
Pubmed
Li,
Characterization of the neuroprotective and toxic effects of alpha7 nicotinic receptor activation in PC12 cells.
1999,
Pubmed
,
Xenbase
Malysz,
In vitro pharmacological characterization of a novel allosteric modulator of alpha 7 neuronal acetylcholine receptor, 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744), exhibiting unique pharmacological profile.
2009,
Pubmed
,
Xenbase
McNerney,
Expression and channel properties of alpha-bungarotoxin-sensitive acetylcholine receptors on chick ciliary and choroid neurons.
2000,
Pubmed
Mike,
Choline and acetylcholine have similar kinetic properties of activation and desensitization on the alpha7 nicotinic receptors in rat hippocampal neurons.
2000,
Pubmed
Millar,
Diversity of vertebrate nicotinic acetylcholine receptors.
2009,
Pubmed
Ng,
Nootropic alpha7 nicotinic receptor allosteric modulator derived from GABAA receptor modulators.
2007,
Pubmed
,
Xenbase
Palma,
Neuronal nicotinic alpha 7 receptor expressed in Xenopus oocytes presents five putative binding sites for methyllycaconitine.
1996,
Pubmed
,
Xenbase
Papke,
alpha7 receptor-selective agonists and modes of alpha7 receptor activation.
2000,
Pubmed
Papke,
Comparative pharmacology of rat and human alpha7 nAChR conducted with net charge analysis.
2002,
Pubmed
,
Xenbase
Papke,
Inhibition of nicotinic acetylcholine receptors by bis (2,2,6,6-tetramethyl- 4-piperidinyl) sebacate (Tinuvin 770), an additive to medical plastics.
1994,
Pubmed
,
Xenbase
Papke,
The correction of alpha7 nicotinic acetylcholine receptor concentration-response relationships in Xenopus oocytes.
1998,
Pubmed
,
Xenbase
Papke,
Molecular dissection of tropisetron, an alpha7 nicotinic acetylcholine receptor-selective partial agonist.
2005,
Pubmed
,
Xenbase
Papke,
Extending the analysis of nicotinic receptor antagonists with the study of alpha6 nicotinic receptor subunit chimeras.
2008,
Pubmed
,
Xenbase
Papke,
Activation and desensitization of nicotinic alpha7-type acetylcholine receptors by benzylidene anabaseines and nicotine.
2009,
Pubmed
,
Xenbase
Papke,
Tricks of perspective: insights and limitations to the study of macroscopic currents for the analysis of nAChR activation and desensitization.
2010,
Pubmed
,
Xenbase
Papke,
Working with OpusXpress: methods for high volume oocyte experiments.
2010,
Pubmed
,
Xenbase
Placzek,
An alpha7 nicotinic acetylcholine receptor gain-of-function mutant that retains pharmacological fidelity.
2005,
Pubmed
,
Xenbase
Qin,
Restoration of single-channel currents using the segmental k-means method based on hidden Markov modeling.
2004,
Pubmed
Skok,
Editorial: To channel or not to channel? Functioning of nicotinic acetylcholine receptors in leukocytes.
2009,
Pubmed
Wang,
Tethered agonist analogs as site-specific probes for domains of the human α7 nicotinic acetylcholine receptor that differentially regulate activation and desensitization.
2010,
Pubmed
,
Xenbase
Williams,
The effective opening of nicotinic acetylcholine receptors with single agonist binding sites.
2011,
Pubmed
,
Xenbase
Williams,
Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics: advantages and limitations.
2011,
Pubmed
Young,
Potentiation of alpha7 nicotinic acetylcholine receptors via an allosteric transmembrane site.
2008,
Pubmed
,
Xenbase
Zhou,
Human alpha4beta2 acetylcholine receptors formed from linked subunits.
2003,
Pubmed
,
Xenbase
del Barrio,
Calcium signalling mediated through α7 and non-α7 nAChR stimulation is differentially regulated in bovine chromaffin cells to induce catecholamine release.
2011,
Pubmed
