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Agonists and antagonists bind to an A-A interface in the heteromeric 5-HT3AB receptor.
Lochner M, Lummis SC.
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The 5-HT3 receptor is a member of the Cys-loop family of transmitter receptors. It can function as a homopentamer (5-HT3A-only subunits) or as a heteropentamer. The 5-HT3AB receptor is the best characterized heteropentamer. This receptor differs from a homopentamer in its kinetics, voltage dependence, and single-channel conductance, but its pharmacology is similar. To understand the contribution of the 5-HT3B subunit to the binding site, we created homology models of 5-HT3AB receptors and docked 5-HT and granisetron into AB, BA, and BB interfaces. To test whether ligands bind in any or all of these interfaces, we mutated amino acids that are important for agonist and antagonist binding in the 5-HT3A subunit to their corresponding residues in the 5-HT3B subunit and vice versa. Changes in [3H]granisetron binding affinity (Kd) and 5-HT EC50 were determined using receptors expressed in HEK-293 cells and Xenopus oocytes, respectively. For all A-to-B mutant receptors, except T181N, antagonist binding was altered or eliminated. Functional studies revealed that either the receptors were nonfunctional or the EC50 values were increased. In B-to-A mutant receptors there were no changes in Kd, although EC50 values and Hill slopes, except for N170T mutant receptors, were similar to those for 5-HT3A receptors. Thus, the experimental data do not support a contribution of the 5-HT3B subunit to the binding pocket, and we conclude that both 5-HT and granisetron bind to an AA binding site in the heteromeric 5-HT3AB receptor.
Barrera,
Atomic force microscopy reveals the stoichiometry and subunit arrangement of 5-HT3 receptors.
2005, Pubmed
Barrera,
Atomic force microscopy reveals the stoichiometry and subunit arrangement of 5-HT3 receptors.
2005,
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 Brejc,
Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors.
2001,
Pubmed Bylund,
Radioligand binding methods: practical guide and tips.
1993,
Pubmed Chen,
Calcium phosphate-mediated gene transfer: a highly efficient transfection system for stably transforming cells with plasmid DNA.
1988,
Pubmed Collingridge,
A nomenclature for ligand-gated ion channels.
2009,
Pubmed Das,
Molecular determinants of picrotoxin inhibition of 5-hydroxytryptamine type 3 receptors.
2005,
Pubmed Davies,
The 5-HT3B subunit is a major determinant of serotonin-receptor function.
1999,
Pubmed
,
Xenbase Dubin,
The pharmacological and functional characteristics of the serotonin 5-HT(3A) receptor are specifically modified by a 5-HT(3B) receptor subunit.
1999,
Pubmed
,
Xenbase Hales,
Common determinants of single channel conductance within the large cytoplasmic loop of 5-hydroxytryptamine type 3 and alpha4beta2 nicotinic acetylcholine receptors.
2006,
Pubmed Hanna,
Evidence for expression of heteromeric serotonin 5-HT(3) receptors in rodents.
2000,
Pubmed Hapfelmeier,
Co-expression of the 5-HT3B serotonin receptor subunit alters the biophysics of the 5-HT3 receptor.
2003,
Pubmed Jordan,
Transfecting mammalian cells: optimization of critical parameters affecting calcium-phosphate precipitate formation.
1996,
Pubmed Joshi,
Interactions of granisetron with an agonist-free 5-HT3A receptor model.
2006,
Pubmed
,
Xenbase Kelley,
A cytoplasmic region determines single-channel conductance in 5-HT3 receptors.
2003,
Pubmed Kunkel,
Rapid and efficient site-specific mutagenesis without phenotypic selection.
1985,
Pubmed Liman,
Subunit stoichiometry of a mammalian K+ channel determined by construction of multimeric cDNAs.
1992,
Pubmed
,
Xenbase Maksay,
Binding interactions of antagonists with 5-hydroxytryptamine3A receptor models.
2003,
Pubmed Melis,
Molecular dynamics simulations of GABA binding to the GABAC receptor: the role of Arg104.
2008,
Pubmed Mu,
Different binding orientations for the same agonist at homologous receptors: a lock and key or a simple wedge?
2003,
Pubmed Niesler,
Cloning, physical mapping and expression analysis of the human 5-HT3 serotonin receptor-like genes HTR3C, HTR3D and HTR3E.
2003,
Pubmed Peters,
The 5-hydroxytryptamine type 3 (5-HT3) receptor reveals a novel determinant of single-channel conductance.
2004,
Pubmed Peters,
Molecular determinants of single-channel conductance and ion selectivity in the Cys-loop family: insights from the 5-HT3 receptor.
2005,
Pubmed Price,
The role of tyrosine residues in the extracellular domain of the 5-hydroxytryptamine3 receptor.
2004,
Pubmed
,
Xenbase Reeves,
Detection of human and rodent 5-HT3B receptor subunits by anti-peptide polyclonal antibodies.
2006,
Pubmed Reeves,
Prediction of 5-HT3 receptor agonist-binding residues using homology modeling.
2003,
Pubmed Reeves,
The molecular basis of the structure and function of the 5-HT3 receptor: a model ligand-gated ion channel (review).
2002,
Pubmed Sali,
Comparative protein modelling by satisfaction of spatial restraints.
1993,
Pubmed Shi,
FUGUE: sequence-structure homology recognition using environment-specific substitution tables and structure-dependent gap penalties.
2001,
Pubmed Spier,
Antibodies against the extracellular domain of the 5-HT3 receptor label both native and recombinant receptors.
1999,
Pubmed Suryanarayanan,
The loop C region of the murine 5-HT3A receptor contributes to the differential actions of 5-hydroxytryptamine and m-chlorophenylbiguanide.
2005,
Pubmed
,
Xenbase Thompson,
Antimalarial drugs inhibit human 5-HT(3) and GABA(A) but not GABA(C) receptors.
2008,
Pubmed
,
Xenbase Thompson,
Locating an antagonist in the 5-HT3 receptor binding site using modeling and radioligand binding.
2005,
Pubmed Tremblay,
Variations in the 5-hydroxytryptamine type 3B receptor gene as predictors of the efficacy of antiemetic treatment in cancer patients.
2003,
Pubmed Turchin,
The primer generator: a program that facilitates the selection of oligonucleotides for site-directed mutagenesis.
1999,
Pubmed Yan,
Spatial orientation of the antagonist granisetron in the ligand-binding site of the 5-HT3 receptor.
2005,
Pubmed
