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Venkataraman, Padmavati; Venkatachalan, Srinivasan P; Joshi, Prasad; Muthalagi, Mani; Schulte, Marvin K.

doi:10.1186/1472-2091-3-15

Cited by 6 publications

(11 citation statements)

References 1 publication

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“…Tyr 143 , however, does not appear to be required for antagonist binding; [ 3 H]granisetron binding affinity is not significantly different from WT when this residue is replaced with phenylalanine, alanine, or serine. This differs from the reports of Venkataraman et al (10), but they do report only a relatively small decrease in affinity (ϳ3-fold).…”

Section: Discussioncontrasting

confidence: 56%

“…The data suggest that more than half of these residues play important roles in either the structure or the function of the receptor. 10) and is one of a selection of radioligands that have been used in similar conditions to probe the binding pocket (6, 9, 21); thus, we can been reasonably confident that this pocket is not significantly altered and that Tyr 73 , Tyr 88 , Tyr 94 , Tyr 167 , and Tyr 240 do not play major roles in either the structure of the extracellular domain or in ligand binding.…”

Section: Discussionmentioning

confidence: 99%

“…In particular a role for tyrosine residues has been demonstrated (8): pretreatment of 5-HT 3 receptors in NG108 -15 cells with the tyrosine-modifying reagent tetranitromethane caused a 30% reduction in specific binding of the 5-HT 3 receptor antagonist [ 3 H]zacopride. In addition, mutation of Tyr 94 to alanine caused a small shift in [ 3 H]granisetron binding affinity (9), and alanine substitutions of Tyr 141 , Tyr 143 , and Tyr 153 have been shown to affect both agonist and antagonist affinities and 5-HT-induced currents (10). Here we extend these studies to examine the radioligand binding, electrophysiological, and cell surface expression properties of mutants of each of the 11 tyrosine residues in the mouse 5-HT 3 receptor extracellular domain.…”

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confidence: 99%

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The Role of Tyrosine Residues in the Extracellular Domain of the 5-Hydroxytryptamine3 Receptor

Price

Lummis

2004

Journal of Biological Chemistry

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Section: Discussioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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The Role of Tyrosine Residues in the Extracellular Domain of the 5-Hydroxytryptamine3 Receptor

Price

Lummis

2004

Journal of Biological Chemistry

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“…specific roles in the binding of granisetron and/or the structure of the binding pocket. There is already evidence from previous studies that the aromatic residues Trp-90, Tyr-153, Trp-195, and Tyr-234 are important in antagonist binding to the 5-HT 3 receptor (27,30,37). The importance of Trp-90 appears to be primarily because of its aromatic nature as removal of the aromatic ring, as in W90A (present study) and W90S (27), eliminates granisetron binding.…”

Section: Fig 2 Representative Examples Of the Three Model Typesmentioning

confidence: 60%

Locating an Antagonist in the 5-HT3 Receptor Binding Site Using Modeling and Radioligand Binding

Thompson

Price

Reeves

et al. 2005

Journal of Biological Chemistry

119

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We have used a homology model of the extracellular domain of the 5-HT 3 receptor to dock granisetron, a 5-HT 3 receptor antagonist, into the binding site using AUTODOCK. This yielded 13 alternative energetically favorable models. The models fell into 3 groups. In model type A the aromatic rings of granisetron were between Trp-90 and Phe-226 and its azabicyclic ring was between Trp-183 and Tyr-234, in model type B this orientation was reversed, and in model type C the aromatic rings were between Asp-229 and Ser-200 and the azabicyclic ring was between Phe-226 and Asn-128. Residues located no more than 5 Å from the docked granisetron were identified for each model; of 26 residues identified, 8 were found to be common to all models, with 18 others being represented in only a subset of the models. To identify which of the docking models best represents the ligand-receptor complex, we substituted each of these 26 residues with alanine and a residue with similar chemical properties. The mutant receptors were expressed in human embryonic kidney (HEK)293 cells and the affinity of granisetron determined using radioligand binding. Mutation of 2 residues (Trp-183 and Glu-129) ablated binding, whereas mutation of 14 other residues caused changes in the [ 3 H]granisetron binding affinity in one or both mutant receptors. The data showed that residues both in and close to the binding pocket can affect antagonist binding and overall were found to best support model B.The 5-HT 3 receptor is the only member of the 5-HT (serotonin) receptor family that is a ligand-gated ion channel. It is a member of the Cys-loop ligand-gated ion channel family, which includes nicotinic acetylcholine (nACh), 1 glycine and GABA A receptors. The receptors function as a pentameric arrangement of subunits. Each subunit has a large extracellular N-terminal region and four transmembrane domains (M1-M4). Five 5-HT 3 receptor subunits (A-E) have been identified although to date only homomeric (A only) or heteromeric (A and B) subunit complexes have been functionally characterized (1, 2). 5-HT 3 receptors may be evolutionarily the oldest members of the Cys-loop family (3), and this, combined with the ability of the A subunit to yield functional homomeric proteins, has meant that 5-HT 3 receptors provide a useful model system for understanding critical features of all Cys loop receptors (4). Most work on this family of proteins has been performed using nACh receptors, but despite many years of study structural details of the receptor-ligand interactions at the atomic level remain unknown. The determination of the structure of the acetylcholinebinding protein (AChBP), which is homologous to the extracellular domain of the nACh receptor, and indeed all Cys loop receptors, has significantly improved our knowledge of the ligand binding domain (5). However, some differences have emerged between the AChBP structure and cryoelectron microscopy data from the nACh receptor. For example, the extracellular domains of the nACh receptor ␣ subunits in the closed state di...

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“…In this context, the three dimensional space of the ligand binding domain is being defined. Numerous tyrosine and tryptophan residues in Loops A–E have a major impact on binding and/or gating, and some differentially interact with agonists (m-chlorophenylbiguanide (m-CPBG)) and antagonists (granisetron and GR65630) (Yan et al, 1999; Spier and Lummis, 2000; Venkataraman et al, 2002; Price and Beene et al, 2004; Lummis, 2004; Yan and White, 2005). For example,W183 in Loop B forms a critical cation-pi interaction with the primary amine of 5-HT (Beene et al, 2002).…”

Section: Introduction To the 5-ht3 Receptor A Ligand-gated Ion Chmentioning

confidence: 99%

Therapeutics of 5-HT3 receptor antagonists: Current uses and future directions

Machu

2011

Pharmacology & Therapeutics

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The 5-Hydroxytryptamine3 (5-HT3) receptor is a member of the cys-loop family of ligand gated ion channels, of which the nicotinic acetylcholine receptor is the prototype. All other 5-HT receptors identified to date are metabotropic receptors. The 5-HT3 receptor is present in the central and peripheral nervous systems, as well as a number of non-nervous tissues. As an ion channel that is permeable to the cations, Na+, K+, and Ca2+, the 5-HT3 receptor mediates fast depolarizing responses in pre- and post-synaptic neurons. As such, 5-HT3 receptor antagonists that are used clinically block afferent and efferent synaptic transmission. The most well established physiological roles of the 5-HT3 receptor are to coordinate emesis and regulate gastrointestinal motility. Currently marketed 5-HT3 receptor antagonists are indicated for treatment of chemotherapy, radiation, and anesthesia-induced nausea and vomiting, as well as irritable bowel syndrome. Other therapeutic uses that have been explored include pain and drug addiction. The 5-HT3 receptor is one of a number of receptors that play a role in mediating nausea and vomiting, and as such, 5-HT3 receptor antagonists demonstrate greatest anti-emetic efficacy when administered in combination with other drug classes.

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Cited by 6 publications

References 1 publication

The Role of Tyrosine Residues in the Extracellular Domain of the 5-Hydroxytryptamine3 Receptor

The Role of Tyrosine Residues in the Extracellular Domain of the 5-Hydroxytryptamine3 Receptor

Locating an Antagonist in the 5-HT3 Receptor Binding Site Using Modeling and Radioligand Binding

Therapeutics of 5-HT3 receptor antagonists: Current uses and future directions

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