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.
J Biol Chem
2014 Feb 14;2897:4515-31. doi: 10.1074/jbc.M113.524603.
Show Gene links
Show Anatomy links
The activity of GAT107, an allosteric activator and positive modulator of α7 nicotinic acetylcholine receptors (nAChR), is regulated by aromatic amino acids that span the subunit interface.
Papke RL
,
Horenstein NA
,
Kulkarni AR
,
Stokes C
,
Corrie LW
,
Maeng CY
,
Thakur GA
.
???displayArticle.abstract???
GAT107, the (+)-enantiomer of racemic 4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide, is a strong positive allosteric modulator (PAM) of α7 nicotinic acetylcholine receptor (nAChR) activation by orthosteric agonists with intrinsic allosteric agonist activities. The direct activation produced by GAT107 in electrophysiological studies is observed only as long as GAT107 is freely diffusible in solution, although the potentiating activity primed by GAT107 can persist for over 30 min after drug washout. Direct activation is sensitive to α7 nAChR antagonist methyllycaconitine, although the primed potentiation is not. The data are consistent with GAT107 activity arising from two different sites. We show that the coupling between PAMs and the binding of orthosteric ligands requires tryptophan 55 (Trp-55), which is located at the subunit interface on the complementary surface of the orthosteric binding site. Mutations of Trp-55 increase the direct activation produced by GAT107 and reduce or prevent the synergy between allosteric and orthosteric binding sites, so that these mutants can also be directly activated by other PAMs such as PNU-120596 and TQS, which do not activate wild-type α7 in the absence of orthosteric agonists. We identify Tyr-93 as an essential element for orthosteric activation, because Y93C mutants are insensitive to orthosteric agonists but respond to GAT107. Our data show that both orthosteric and allosteric activation of α7 nAChR require cooperative activity at the interface between the subunits in the extracellular domain. These cooperative effects rely on key aromatic residues, and although mutations of Trp-55 reduce the restraints placed on the requirement for orthosteric agonists, Tyr-93 can conduct both orthosteric activation and desensitization among the subunits.
Akk,
Aromatics at the murine nicotinic receptor agonist binding site: mutational analysis of the alphaY93 and alphaW149 residues.
2001, Pubmed
Akk,
Aromatics at the murine nicotinic receptor agonist binding site: mutational analysis of the alphaY93 and alphaW149 residues.
2001,
Pubmed
Bencherif,
Alpha7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases.
2011,
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
Brejc,
The 2.7 A structure of AChBP, homologue of the ligand-binding domain of the nicotinic acetylcholine receptor.
2002,
Pubmed
Briggs,
Role of channel activation in cognitive enhancement mediated by alpha7 nicotinic acetylcholine receptors.
2009,
Pubmed
,
Xenbase
Callahan,
Positive allosteric modulator of α7 nicotinic-acetylcholine receptors, PNU-120596 augments the effects of donepezil on learning and memory in aged rodents and non-human primates.
2013,
Pubmed
Corringer,
Critical elements determining diversity in agonist binding and desensitization of neuronal nicotinic acetylcholine receptors.
1998,
Pubmed
,
Xenbase
Freitas,
The antinociceptive effects of nicotinic receptors α7-positive allosteric modulators in murine acute and tonic pain models.
2013,
Pubmed
Gay,
Aromatic residues at position 55 of rat alpha7 nicotinic acetylcholine receptors are critical for maintaining rapid desensitization.
2008,
Pubmed
,
Xenbase
Gill,
Agonist activation of alpha7 nicotinic acetylcholine receptors via an allosteric transmembrane site.
2011,
Pubmed
,
Xenbase
Grønlien,
Distinct profiles of alpha7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes.
2007,
Pubmed
,
Xenbase
Hajós,
Targeting alpha7 nicotinic acetylcholine receptors in the treatment of schizophrenia.
2010,
Pubmed
Halevi,
Conservation within the RIC-3 gene family. Effectors of mammalian nicotinic acetylcholine receptor expression.
2003,
Pubmed
,
Xenbase
Horenstein,
Reversal of agonist selectivity by mutations of conserved amino acids in the binding site of nicotinic acetylcholine receptors.
2007,
Pubmed
,
Xenbase
Kalappa,
A positive allosteric modulator of α7 nAChRs augments neuroprotective effects of endogenous nicotinic agonists in cerebral ischaemia.
2013,
Pubmed
Kulkarni,
Microwave-assisted Expeditious and Efficient Synthesis of Cyclopentene Ring-fused Tetrahydroquinoline Derivatives Using Three-component Povarov Reaction.
2013,
Pubmed
Le Novère,
The diversity of subunit composition in nAChRs: evolutionary origins, physiologic and pharmacologic consequences.
2002,
Pubmed
Leiser,
A cog in cognition: how the alpha 7 nicotinic acetylcholine receptor is geared towards improving cognitive deficits.
2009,
Pubmed
Munro,
The α7 nicotinic ACh receptor agonist compound B and positive allosteric modulator PNU-120596 both alleviate inflammatory hyperalgesia and cytokine release in the rat.
2012,
Pubmed
Papke,
Comparative pharmacology of rat and human alpha7 nAChR conducted with net charge analysis.
2002,
Pubmed
,
Xenbase
Papke,
Working with OpusXpress: methods for high volume oocyte experiments.
2010,
Pubmed
,
Xenbase
Papke,
An evaluation of neuronal nicotinic acetylcholine receptor activation by quaternary nitrogen compounds indicates that choline is selective for the alpha 7 subtype.
1996,
Pubmed
,
Xenbase
Papke,
Cysteine accessibility analysis of the human alpha7 nicotinic acetylcholine receptor ligand-binding domain identifies L119 as a gatekeeper.
2011,
Pubmed
,
Xenbase
Peng,
Multiple modes of α7 nAChR noncompetitive antagonism of control agonist-evoked and allosterically enhanced currents.
2013,
Pubmed
,
Xenbase
Sitzia,
Voltage- and Temperature-Dependent Allosteric Modulation of α7 Nicotinic Receptors by PNU120596.
2011,
Pubmed
Stewart,
Mapping the structural requirements for nicotinic acetylcholine receptor activation by using tethered alkyltrimethylammonium agonists and antagonists.
2006,
Pubmed
,
Xenbase
Taly,
Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system.
2009,
Pubmed
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
Thomsen,
Differential immediate and sustained memory enhancing effects of alpha7 nicotinic receptor agonists and allosteric modulators in rats.
2011,
Pubmed
Thomsen,
The α7 nicotinic acetylcholine receptor ligands methyllycaconitine, NS6740 and GTS-21 reduce lipopolysaccharide-induced TNF-α release from microglia.
2012,
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
Wang,
Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation.
2003,
Pubmed
Williams,
Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics: advantages and limitations.
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,
Intrinsically low open probability of α7 nicotinic acetylcholine receptors can be overcome by positive allosteric modulation and serum factors leading to the generation of excitotoxic currents at physiological temperatures.
2012,
Pubmed
,
Xenbase
Williams,
The effective opening of nicotinic acetylcholine receptors with single agonist binding sites.
2011,
Pubmed
,
Xenbase
Williams,
Differential regulation of receptor activation and agonist selectivity by highly conserved tryptophans in the nicotinic acetylcholine receptor binding site.
2009,
Pubmed
,
Xenbase
Young,
Potentiation of alpha7 nicotinic acetylcholine receptors via an allosteric transmembrane site.
2008,
Pubmed
,
Xenbase
de Jonge,
The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation.
2007,
Pubmed
