Pharmacological comparison of human homomeric 5-HT3A receptors versus heteromeric 5-HT3A/3B receptors

Brady, Catherine; Stanford, Ian M.; Ali, Ibrahim A. I.; Lin, Lin; Williams, Julie M.; Dubin, Adrienne E.; Hope, Anthony G.; Barnes, Nicholas M.

doi:10.1016/s0028-3908(01)00074-0

Cited by 88 publications

(76 citation statements)

References 10 publications

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“…Of the heteromeric receptors, only 5-HT 3 AB receptors have been extensively characterized and, compared to homomeric 5-HT 3 A, 5-HT 3 AB receptors differ in their EC 50 , Hill slope, desensitization kinetics, shape of current-voltage relationship, and most noticeably, a much larger single-channel conductance (y16 pS in 5-HT 3 AB compared to <1 pS in 5-HT 3 A ; Davies et al 1999 ;Dubin et al 1999). However, the pharmacology of 5-HT 3 A and 5-HT 3 AB receptors is almost identical, suggesting that they contain a common binding site (an A-A interface), a hypothesis supported by a recent study of mouse 5-HT 3 AB receptors (Brady et al 2001 ;, but conflicting with the BABBA arrangement determined using atomic force microscopy (Barrera et al 2005). The subunit types and stoichiometry of 5-HT 3 Rs have been recently reviewed (Barnes et al 2009 ;Jensen et al 2008).…”

Section: +mentioning

confidence: 99%

The structural basis of function in Cys-loop receptors

Thompson

Lester

Lummis

2010

Quart. Rev. Biophys.

322

398

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Abstract. Cys-loop receptors are membrane-spanning neurotransmitter-gated ion channels that are responsible for fast excitatory and inhibitory transmission in the peripheral and central nervous systems. The best studied members of the Cys-loop family are nACh, 5-HT 3 , GABA A and glycine receptors. All these receptors share a common structure of five subunits, pseudo-symmetrically arranged to form a rosette with a central ion-conducting pore. Some are cation selective (e.g. nACh and 5-HT 3 ) and some are anion selective (e.g. GABA A and glycine). Each receptor has an extracellular domain (ECD) that contains the ligand-binding sites, a transmembrane domain (TMD) that allows ions to pass across the membrane, and an intracellular domain (ICD) that plays a role in channel conductance and receptor modulation. Cys-loop receptors are the targets for many currently used clinically relevant drugs (e.g. benzodiazepines and anaesthetics). Understanding the molecular mechanisms of these receptors could therefore provide the catalyst for further development in this field, as well as promoting the development of experimental techniques for other areas of neuroscience.In this review, we present our current understanding of Cys-loop receptor structure and function. The ECD has been extensively studied. Research in this area has been stimulated in recent years by the publication of high-resolution structures of nACh receptors and related proteins, which have permitted the creation of many Cys loop receptor homology models of this region. Here, using the 5-HT 3 receptor as a typical member of the family, we describe how homology modelling and ligand docking can provide useful but not definitive information about ligand interactions. We briefly consider some of the many Cys-loop receptors modulators. We discuss the current understanding of the structure of the TMD, and how this links to the ECD to allow channel gating, and consider the roles of the ICD, whose structure is poorly understood. We also describe some of the current methods that are beginning to reveal the differences between different receptor states, and may ultimately show structural details of transitions between them.

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Section: +mentioning

confidence: 99%

The structural basis of function in Cys-loop receptors

Thompson

Lester

Lummis

2010

Quart. Rev. Biophys.

322

398

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“…Competitive antagonists of 5-HT 3 receptors are used clinically as antiemetics in cancer chemotherapy and in general anesthesia, although other applications are being explored (13). The two receptor subtypes are difficult to distinguish pharmacologically (14), although picrotoxin (15) and tubocurarine (7) are markedly less potent in blocking agonist-induced currents in the exogenously expressed heteromeric receptors. Although there is some anatomical evidence that the homomeric receptor may be expressed alone in the rat (16,17), current functional evidence suggests that it is the heteromer that is of major importance both centrally and in the periphery.…”

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confidence: 99%

Atomic force microscopy reveals the stoichiometry and subunit arrangement of 5-HT₃receptors

Barrera

Herbert

Henderson

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

111

104

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The 5-HT3 receptor is a cation-selective ligand-gated ion channel of the Cys-loop superfamily. The receptor is an important therapeutic target, with receptor antagonists being widely used as antiemetics in cancer therapy. The two known receptor subunits, A and B, form homomeric 5-HT 3A receptors and heteromeric 5-HT3A/B receptors. The heteromeric receptor has the higher single-channel conductance and more closely mimics the properties of the native receptor. We have used atomic force microscopy to study the architecture of 5-HT 3A and 5-HT3A/B receptors. We engineered different epitope tags onto the A-and B-subunits and imaged receptors that were doubly liganded by anti-epitope antibodies. We found that, for the 5-HT 3A/B receptor, the distribution of angles between antibodies against the A-subunit had a single peak at Ϸ144°, whereas the distribution for antibodies against the B-subunit had two peaks at Ϸ72°and 144°. Our results indicate that the subunit stoichiometry is 2A:3B and that the subunit arrangement around the receptor rosette is B-B-A-B-A. This arrangement may account for the difference between the agonist Hill coefficients and the single-channel conductances for the two types of receptor.ligand-gated ion channel ͉ receptor structure T he 5-HT 3 receptor is a member of the Cys-loop ligand-gated ion channel superfamily, together with the nicotinic acetylcholine receptor, the GABA A receptor, and the glycine receptor (1-3). Electron microscopy of the affinity purified 5-HT 3 receptor has shown that it contains five subunits arranged pseudosymmetrically around a cylinder of long axis 11 nm and external diameter 8 nm (4, 5). The vestibule of the channel, normally open to the cell exterior, is visible as an opening of diameter 2-3 nm. Two 5-HT 3 receptor subunits have been investigated in detail. The first to be cloned, 5-HT 3A (6), expresses as a functional homomer, whereas the second, 5-HT 3B , is unable to form functional channels alone but expresses robustly in the presence of the 5-HT 3A subunit (7). The genes for these two subunits are located in close proximity on chromosome 11, although additional putative 5-HT 3 receptor genes have been isolated on chromosome 3 (8). The biophysical properties of the 5-HT 3A and the 5-HT 3A/B receptors exhibit significant differences, with those of the heteromer more closely resembling those of the receptor characterized within the majority of mammalian systems (9-12). Competitive antagonists of 5-HT 3 receptors are used clinically as antiemetics in cancer chemotherapy and in general anesthesia, although other applications are being explored (13). The two receptor subtypes are difficult to distinguish pharmacologically (14), although picrotoxin (15) and tubocurarine (7) are markedly less potent in blocking agonist-induced currents in the exogenously expressed heteromeric receptors. Although there is some anatomical evidence that the homomeric receptor may be expressed alone in the rat (16, 17), current functional evidence suggests that it is the heteromer that is o...

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“…Only 5-HT 3A subunits are able to form functional homo-oligomeric receptors, whereas the 5-HT 3B , C , D and E subunits cannot build a functional homopentameric receptor on their own [1-3,5,6]. Although heteromeric 5-HT 3A/X receptors show individual differences compared to homomeric 5-HT 3A receptors, the overall pharmacological profiles are similar [3,7]. By contrast, structurally different compounds and 5-HT 3 receptors of diverse composition may very likely present distinct pharmacological properties.…”

Section: Human 5-ht 3 Receptor Systemmentioning

confidence: 99%

Serotonin Type 3 Receptor Genes: HTR3A, B, C, D, E

et al. 2008

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The 5-HT 3 receptor is a ligand-gated ion channel composed of five subunits. To date, five different human subunits are known, 5-HT 3A-E , which are encoded by the serotonin receptor genes HTR3A, HTR3B, HTR3C, HTR3D and HTR3E, respectively. Functional receptors are pentameric complexes of diverse composition. Different receptor subtypes seem to be involved in chemotherapyinduced nausea and vomiting (CINV), irritable bowel syndrome and psychiatric disorders. 5-HT 3 receptor antagonists are established in the therapy of CINV and irritable bowel syndrome. HTR3A and HTR3B polymorphisms may also contribute to the etiology of psychiatric disorders and serve as predictors in CINV and in the medical treatment of psychiatric patients.

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Pharmacological comparison of human homomeric 5-HT3A receptors versus heteromeric 5-HT3A/3B receptors

Cited by 88 publications

References 10 publications

The structural basis of function in Cys-loop receptors

The structural basis of function in Cys-loop receptors

Atomic force microscopy reveals the stoichiometry and subunit arrangement of 5-HT₃receptors

Serotonin Type 3 Receptor Genes: HTR3A, B, C, D, E

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Pharmacological comparison of human homomeric 5-HT3A receptors versus heteromeric 5-HT3A/3B receptors

Cited by 88 publications

References 10 publications

The structural basis of function in Cys-loop receptors

The structural basis of function in Cys-loop receptors

Atomic force microscopy reveals the stoichiometry and subunit arrangement of 5-HT3receptors

Serotonin Type 3 Receptor Genes: HTR3A, B, C, D, E

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Atomic force microscopy reveals the stoichiometry and subunit arrangement of 5-HT₃receptors