Tissue-specific alternative promoters of the serotonin receptor gene HTR3B in human brain and intestine

Tzvetkov, Mladen V.; Meineke, Cornelia; Oetjen, Elke; Hirsch‐Ernst, Karen Ildico; Brockmöller, Jürgen

doi:10.1016/j.gene.2006.08.002

Cited by 59 publications

(57 citation statements)

References 30 publications

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“…The 5-HT 3 R is an example of a Cys-loop receptor with relatively few subunits ; five have been identified to date (A-E), although like many other receptors, some of these demonstrate a further level of complexity that results from different splice-variations and differing post-translational modifications (Bruss et al 2000 ;Tzvetkov et al 2007 ;Werner et al 1994). For example, there are long and short forms of the mouse 5-HT3A subunit that differ by six amino acids, and there are three translational variants of the human 5-HT3B subunit (Fig.…”

Section: +mentioning

confidence: 99%

The structural basis of function in Cys-loop receptors

Thompson

Lester

Lummis

2010

Quart. Rev. Biophys.

326

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.

326

398

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“…Intriguingly, a transcriptional control that gives rise to different isoforms of the HTR3B has been reported, characterizing the 5′ coding ending in a specific way for the CNS. 264 An association with vomiting and nausea, both caused by chemotherapy and paroxetine, was reported with the -100 -102 AAG deletion variant of HTR3B. 265 Conflicting findings were reported for the HTR3A 195C>T (rs62625041) and 178C>T SNPs with respect to the gastrointestinal side effects induced by SSRIs, 52,190,266 whereas the HTR3B polymorphism at position 129 leading to a tyrosine-to-serine substitution (rs1176744) was found to be associated with nausea induced by paroxetine, 266 but conflicting findings have been reported.…”

Section: Serotonin 3a and 3bmentioning

confidence: 99%

Pharmacogenetics of antidepressant response

Porcelli

Drago

Fabbri

et al. 2011

J Psychiatry Neurosci

160

103

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87Personalized medicine -the adaptation of therapies based on an individual's genetic and molecular profile -is one of the most promising aspects of modern medicine. The identification of the relation between genotype and drug response, including both the therapeutic effect and side effect profile, is expected to deeply affect medical practice. In this paper, we review the current knowledge about the genes related to antidepressant treatment response and provide methodologic proposals for future studies. We have mainly focused on genes associated with pharmacodynamics, for which a list of promising genes has been identified despite some inconsistency across studies. We have also synthesized the main results for pharmacokinetic genes, although so far they seem less relevant than those for pharmaco dynamic genes. We discuss possible reasons for these inconsistent findings and propose new study designs.

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“…In the human nervous system, 5-HT 3 A subunits have been found throughout the adult brain, but are also widely distributed in extraneuronal cells (Miyake et al, 1995;Fiebich et al, 2004). 5-HT 3 B receptor subunits are not as widespread, but are still detectable in a range of tissues (Davies et al, 1999;Dubin et al, 1999;Niesler et al, 2003;Tzvetkov et al, 2007). The other subunits have been less well studied, and their functional significance is not yet clear (Thompson et al, 2010a).…”

Section: Introductionmentioning

confidence: 99%

Varenicline Is a Potent Agonist of the Human 5-Hydroxytryptamine₃ Receptor

Lummis¹,

Thompson²,

Bencherif³

et al. 2011

J Pharmacol Exp Ther

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Varenicline, a widely used and successful smoking cessation agent, acts as a partial agonist at nicotinic acetylcholine receptors. Here, we explore the effects of varenicline at human and mouse 5-Hydroxytryptamine 3 (5-HT 3 ) receptors. Application of varenicline to human 5-HT 3 receptors expressed in Xenopus laevis oocytes reveal it is almost a full agonist (R max ϭ 80%) with an EC 50 (5.9 M) 3-fold higher than 5-HT. At mouse 5-HT 3 receptors varenicline is a partial agonist (R max ϭ 35%) with an EC 50 (18 M) 20-fold higher than 5-HT. Displacement of the competitive 5-HT 3 receptor antagonist [ 3 H]granisetron reveals similar IC 50 values for varenicline at mouse and human receptors expressed in human embryonic kidney 293 cells, although studies in these cells using a membrane potential-sensitive dye show that again varenicline is a 4-or 35-fold less potent agonist than 5-HT in human and mouse receptors, respectively. Thus the data suggest that the efficacy, but not the affinity, of varenicline is greater at human 5-HT 3 receptors compared with mouse. Docking studies provide a possible explanation for this difference, because they suggest distinct orientations of the ligand in the mouse versus human 5-HT 3 agonist binding sites. Additional binding selectivity studies in a broad panel of recombinant receptors and enzymes confirmed an interaction with 5-HT 3 receptors but revealed no additional interactions of varenicline. Therefore, activation of human 5-HT 3 receptors may be responsible for some of the side effects that preclude use of higher doses during varenicline treatment.

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Tissue-specific alternative promoters of the serotonin receptor gene HTR3B in human brain and intestine

Cited by 59 publications

References 30 publications

The structural basis of function in Cys-loop receptors

The structural basis of function in Cys-loop receptors

Pharmacogenetics of antidepressant response

Varenicline Is a Potent Agonist of the Human 5-Hydroxytryptamine₃ Receptor

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Tissue-specific alternative promoters of the serotonin receptor gene HTR3B in human brain and intestine

Cited by 59 publications

References 30 publications

The structural basis of function in Cys-loop receptors

The structural basis of function in Cys-loop receptors

Pharmacogenetics of antidepressant response

Varenicline Is a Potent Agonist of the Human 5-Hydroxytryptamine3 Receptor

Contact Info

Product

Resources

About

Varenicline Is a Potent Agonist of the Human 5-Hydroxytryptamine₃ Receptor