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.
Differential regulation of receptor activation and agonist selectivity by highly conserved tryptophans in the nicotinic acetylcholine receptor binding site.
Williams DK, Stokes C, Horenstein NA, Papke RL.
???displayArticle.abstract???
We have shown previously that a highly conserved Tyr in the nicotinic acetylcholine receptor (nAChR) ligand-binding domain (LBD) (alpha7 Tyr188 or alpha4 Tyr195) differentially regulates the activity of acetylcholine (ACh) and the alpha7-selective agonist 3-(4-hydroxy,2-methoxybenzylidene)anabaseine (4OH-GTS-21) in alpha4beta2 and alpha7 nAChR. In this study, we mutated two highly conserved LBD Trp residues in human alpha7 and alpha4beta2 and expressed the receptors in Xenopus laevis oocytes. Alpha7 receptors with Trp55 mutated to Gly or Tyr became less responsive to 4OH-GTS-21, whereas mutation of the homologous Trp57 in beta2 to Gly, Tyr, Phe, or Ala resulted in alpha4beta2 receptors that showed increased responses to 4OH-GTS-21. Mutation of alpha7 Trp55 to Val resulted in receptors for which the partial agonist 4OH-GTS-21 became equally efficacious as ACh, whereas alpha4beta2 receptors with the homologous mutation remained nonresponsive to 4OH-GTS-21. In contrast to the striking alterations in agonist activity profiles that were observed with mutations of alpha7 Trp55 and beta2 Trp57, mutations of alpha7 Trp149 or alpha4 Trp154 universally resulted in receptors with reduced function. Our data support the hypothesis that some conserved residues in the nAChR LBD differentially regulate receptor activation by subtype-selective agonists, whereas other equally well conserved residues play fundamental roles in receptor activation by any agonist. Residues like alpha7 Trp149 (alpha4 Trp154) may be considered pillars upon which basic receptor function depends, whereas alpha7 Trp55 (beta2 Trp57) and alpha7 Tyr188 (alpha4 Tyr195) may be fulcra upon which agonists may operate differentially in specific receptor subtypes, consistent with the hypothesis that ACh and 4OH-GTS-21 are able to activate nAChR in distinct ways.
Arnold,
The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling.
2006, Pubmed
Arnold,
The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling.
2006,
Pubmed Aylwin,
Ligand-receptor interactions in the nicotinic acetylcholine receptor probed using multiple substitutions at conserved tyrosines on the alpha subunit.
1994,
Pubmed
,
Xenbase 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 Chiara,
Identification of tryptophan 55 as the primary site of [3H]nicotine photoincorporation in the gamma-subunit of the Torpedo nicotinic acetylcholine receptor.
1998,
Pubmed Chiara,
Identification of amino acids contributing to high and low affinity d-tubocurarine sites in the Torpedo nicotinic acetylcholine receptor.
1997,
Pubmed Cohen,
Structure of the agonist-binding site of the nicotinic acetylcholine receptor. [3H]acetylcholine mustard identifies residues in the cation-binding subsite.
1991,
Pubmed Dani,
Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system.
2007,
Pubmed Devillers-Thiéry,
Functional architecture of the nicotinic acetylcholine receptor: a prototype of ligand-gated ion channels.
1993,
Pubmed Francis,
Specific activation of the alpha 7 nicotinic acetylcholine receptor by a quaternary analog of cocaine.
2001,
Pubmed
,
Xenbase Galzi,
Functional significance of aromatic amino acids from three peptide loops of the alpha 7 neuronal nicotinic receptor site investigated by site-directed mutagenesis.
1991,
Pubmed
,
Xenbase Galzi,
Neuronal nicotinic receptors: molecular organization and regulations.
1995,
Pubmed Gay,
Aromatic residues at position 55 of rat alpha7 nicotinic acetylcholine receptors are critical for maintaining rapid desensitization.
2008,
Pubmed
,
Xenbase Gotti,
Brain nicotinic acetylcholine receptors: native subtypes and their relevance.
2006,
Pubmed Halevi,
Conservation within the RIC-3 gene family. Effectors of mammalian nicotinic acetylcholine receptor expression.
2003,
Pubmed
,
Xenbase Hansen,
Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations.
2005,
Pubmed 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 Higgins,
Using CLUSTAL for multiple sequence alignments.
1996,
Pubmed Horenstein,
Reversal of agonist selectivity by mutations of conserved amino acids in the binding site of nicotinic acetylcholine receptors.
2007,
Pubmed
,
Xenbase Kalamida,
Muscle and neuronal nicotinic acetylcholine receptors. Structure, function and pathogenicity.
2007,
Pubmed Kopp,
The SWISS-MODEL Repository of annotated three-dimensional protein structure homology models.
2004,
Pubmed Kuryatov,
Roles of accessory subunits in alpha4beta2(*) nicotinic receptors.
2008,
Pubmed Moustakas,
Development and validation of a modular, extensible docking program: DOCK 5.
2006,
Pubmed Mu,
Different binding orientations for the same agonist at homologous receptors: a lock and key or a simple wedge?
2003,
Pubmed O'Leary,
Mutational analysis of ligand-induced activation of the Torpedo acetylcholine receptor.
1992,
Pubmed
,
Xenbase Ortells,
Evolutionary history of the ligand-gated ion-channel superfamily of receptors.
1995,
Pubmed Papke,
The correction of alpha7 nicotinic acetylcholine receptor concentration-response relationships in Xenopus oocytes.
1998,
Pubmed
,
Xenbase Papke,
Estimation of both the potency and efficacy of alpha7 nAChR agonists from single-concentration responses.
2006,
Pubmed
,
Xenbase Papke,
Activation and desensitization of nicotinic alpha7-type acetylcholine receptors by benzylidene anabaseines and nicotine.
2009,
Pubmed
,
Xenbase Papke,
Comparative pharmacology of rat and human alpha7 nAChR conducted with net charge analysis.
2002,
Pubmed
,
Xenbase Pettersen,
UCSF Chimera--a visualization system for exploratory research and analysis.
2004,
Pubmed Schwede,
SWISS-MODEL: An automated protein homology-modeling server.
2003,
Pubmed Sine,
Conserved tyrosines in the alpha subunit of the nicotinic acetylcholine receptor stabilize quaternary ammonium groups of agonists and curariform antagonists.
1994,
Pubmed
,
Xenbase Tasneem,
Identification of the prokaryotic ligand-gated ion channels and their implications for the mechanisms and origins of animal Cys-loop ion channels.
2005,
Pubmed Tomaselli,
Mutations affecting agonist sensitivity of the nicotinic acetylcholine receptor.
1991,
Pubmed
,
Xenbase Xie,
Contributions of Torpedo nicotinic acetylcholine receptor gamma Trp-55 and delta Trp-57 to agonist and competitive antagonist function.
2001,
Pubmed
,
Xenbase Xiu,
Nicotine binding to brain receptors requires a strong cation-pi interaction.
2009,
Pubmed
,
Xenbase Zhong,
From ab initio quantum mechanics to molecular neurobiology: a cation-pi binding site in the nicotinic receptor.
1998,
Pubmed
