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.
Two neuronal nicotinic acetylcholine receptors, alpha4beta4 and alpha7, show differential agonist binding modes.
Puskar NL
,
Xiu X
,
Lester HA
,
Dougherty DA
.
???displayArticle.abstract???
Nicotinic acetylcholine receptors (nAChRs) are pentameric, neurotransmitter-gated ion channels responsible for rapid excitatory neurotransmission in the central and peripheral nervous systems, resulting in skeletal muscle tone and various cognitive effects in the brain. These complex proteins are activated by the endogenous neurotransmitter ACh as well as by nicotine and structurally related agonists. Activation and modulation of nAChRs has been implicated in the pathology of multiple neurological disorders, and as such, these proteins are established therapeutic targets. Here we use unnatural amino acid mutagenesis to examine the ligand binding mechanisms of two homologous neuronal nAChRs: the α4β4 and α7 receptors. Despite sequence identity among the residues that form the core of the agonist-binding site, we find that the α4β4 and α7 nAChRs employ different agonist-receptor binding interactions in this region. The α4β4 receptor utilizes a strong cation-π interaction to a conserved tryptophan (TrpB) of the receptor for both ACh and nicotine, and nicotine participates in a strong hydrogen bond with a backbone carbonyl contributed by TrpB. Interestingly, we find that the α7 receptor also employs a cation-π interaction for ligand recognition, but the site has moved to a different aromatic amino acid of the agonist-binding site depending on the agonist. ACh participates in a cation-π interaction with TyrA, whereas epibatidine participates in a cation-π interaction with TyrC2.
Alkondon,
Choline is a selective agonist of alpha7 nicotinic acetylcholine receptors in the rat brain neurons.
1997, Pubmed
Alkondon,
Choline is a selective agonist of alpha7 nicotinic acetylcholine receptors in the rat brain neurons.
1997,
Pubmed
Beene,
Cation-pi interactions in ligand recognition by serotonergic (5-HT3A) and nicotinic acetylcholine receptors: the anomalous binding properties of nicotine.
2002,
Pubmed
,
Xenbase
Beers,
Structure and activity of acetylcholine.
1970,
Pubmed
Ben-Ami,
RIC-3 affects properties and quantity of nicotinic acetylcholine receptors via a mechanism that does not require the coiled-coil domains.
2005,
Pubmed
,
Xenbase
Blum,
Nicotinic pharmacophore: the pyridine N of nicotine and carbonyl of acetylcholine hydrogen bond across a subunit interface to a backbone NH.
2010,
Pubmed
,
Xenbase
Brejc,
Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors.
2001,
Pubmed
Cashin,
Using physical chemistry to differentiate nicotinic from cholinergic agonists at the nicotinic acetylcholine receptor.
2005,
Pubmed
,
Xenbase
Castillo,
Dual role of the RIC-3 protein in trafficking of serotonin and nicotinic acetylcholine receptors.
2005,
Pubmed
,
Xenbase
Cheng,
Cell surface expression of 5-hydroxytryptamine type 3 receptors is promoted by RIC-3.
2005,
Pubmed
Corringer,
Nicotinic receptors at the amino acid level.
2000,
Pubmed
Court,
Nicotinic and muscarinic cholinergic receptor binding in the human hippocampal formation during development and aging.
1997,
Pubmed
Dart,
Structural aspects of high affinity ligands for the alpha 4 beta 2 neuronal nicotinic receptor.
2000,
Pubmed
Dougherty,
Cys-loop neuroreceptors: structure to the rescue?
2008,
Pubmed
Dougherty,
Cation-pi interactions in chemistry and biology: a new view of benzene, Phe, Tyr, and Trp.
1996,
Pubmed
Espinoza-Fonseca,
Fully flexible docking models of the complex between alpha7 nicotinic receptor and a potent heptapeptide inhibitor of the beta-amyloid peptide binding.
2006,
Pubmed
Gallivan,
Cation-pi interactions in structural biology.
1999,
Pubmed
Glennon,
Central nicotinic receptor ligands and pharmacophores.
2000,
Pubmed
Gotti,
Neuronal nicotinic receptors: from structure to pathology.
2004,
Pubmed
Grutter,
An H-bond between two residues from different loops of the acetylcholine binding site contributes to the activation mechanism of nicotinic receptors.
2003,
Pubmed
Halevi,
The C. elegans ric-3 gene is required for maturation of nicotinic acetylcholine receptors.
2002,
Pubmed
,
Xenbase
Improgo,
The nicotinic acetylcholine receptor CHRNA5/A3/B4 gene cluster: dual role in nicotine addiction and lung cancer.
2010,
Pubmed
Jensen,
Neuronal nicotinic acetylcholine receptors: structural revelations, target identifications, and therapeutic inspirations.
2005,
Pubmed
Lummis,
A cation-pi binding interaction with a tyrosine in the binding site of the GABAC receptor.
2005,
Pubmed
Martin,
Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia.
2004,
Pubmed
Moroni,
alpha4beta2 nicotinic receptors with high and low acetylcholine sensitivity: pharmacology, stoichiometry, and sensitivity to long-term exposure to nicotine.
2006,
Pubmed
,
Xenbase
Mu,
Different binding orientations for the same agonist at homologous receptors: a lock and key or a simple wedge?
2003,
Pubmed
Nelson,
Alternate stoichiometries of alpha4beta2 nicotinic acetylcholine receptors.
2003,
Pubmed
,
Xenbase
Nowak,
In vivo incorporation of unnatural amino acids into ion channels in Xenopus oocyte expression system.
1998,
Pubmed
,
Xenbase
Nowak,
Nicotinic receptor binding site probed with unnatural amino acid incorporation in intact cells.
1995,
Pubmed
,
Xenbase
O'Neill,
The role of neuronal nicotinic acetylcholine receptors in acute and chronic neurodegeneration.
2002,
Pubmed
Orr-Urtreger,
Mice deficient in the alpha7 neuronal nicotinic acetylcholine receptor lack alpha-bungarotoxin binding sites and hippocampal fast nicotinic currents.
1997,
Pubmed
Padgett,
Unnatural amino acid mutagenesis of the GABA(A) receptor binding site residues reveals a novel cation-pi interaction between GABA and beta 2Tyr97.
2007,
Pubmed
,
Xenbase
Parker,
Neuronal nicotinic receptor beta2 and beta4 subunits confer large differences in agonist binding affinity.
1998,
Pubmed
,
Xenbase
Placzek,
An alpha7 nicotinic acetylcholine receptor gain-of-function mutant that retains pharmacological fidelity.
2005,
Pubmed
,
Xenbase
Romanelli,
Central nicotinic receptors: structure, function, ligands, and therapeutic potential.
2007,
Pubmed
Saks,
An engineered Tetrahymena tRNAGln for in vivo incorporation of unnatural amino acids into proteins by nonsense suppression.
1996,
Pubmed
,
Xenbase
Séguéla,
Molecular cloning, functional properties, and distribution of rat brain alpha 7: a nicotinic cation channel highly permeable to calcium.
1993,
Pubmed
,
Xenbase
Sixma,
Acetylcholine binding protein (AChBP): a secreted glial protein that provides a high-resolution model for the extracellular domain of pentameric ligand-gated ion channels.
2003,
Pubmed
Stevens,
Selective alpha7-nicotinic agonists normalize inhibition of auditory response in DBA mice.
1998,
Pubmed
Stevens,
Genetic correlation of inhibitory gating of hippocampal auditory evoked response and alpha-bungarotoxin-binding nicotinic cholinergic receptors in inbred mouse strains.
1996,
Pubmed
Torrice,
Probing the role of the cation-pi interaction in the binding sites of GPCRs using unnatural amino acids.
2009,
Pubmed
,
Xenbase
Trombino,
Alpha7-nicotinic acetylcholine receptors affect growth regulation of human mesothelioma cells: role of mitogen-activated protein kinase pathway.
2004,
Pubmed
Unwin,
Refined structure of the nicotinic acetylcholine receptor at 4A resolution.
2005,
Pubmed
Vijayaraghavan,
Nicotinic receptors that bind alpha-bungarotoxin on neurons raise intracellular free Ca2+.
1992,
Pubmed
Wang,
Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation.
2003,
Pubmed
Williams,
Ric-3 promotes functional expression of the nicotinic acetylcholine receptor alpha7 subunit in mammalian cells.
2005,
Pubmed
,
Xenbase
Wu,
Roles of nicotinic acetylcholine receptor beta subunits in function of human alpha4-containing nicotinic receptors.
2006,
Pubmed
Xiu,
Nicotine binding to brain receptors requires a strong cation-pi interaction.
2009,
Pubmed
,
Xenbase
Zeisel,
Choline: critical role during fetal development and dietary requirements in adults.
2006,
Pubmed
Zhang,
Neuronal acetylcholine receptors that bind alpha-bungarotoxin with high affinity function as ligand-gated ion channels.
1994,
Pubmed
,
Xenbase
Zhong,
From ab initio quantum mechanics to molecular neurobiology: a cation-pi binding site in the nicotinic receptor.
1998,
Pubmed
