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Concept: 5-HT receptor


5-hydroxytryptamine (5-HT, also known as serotonin) regulates many physiological processes through the 5-HT receptor family. Here we report the crystal structure of 5-HT1B subtype receptor (5-HT1BR) bound to the psychotropic serotonin receptor inverse agonist methiothepin (MT). Crystallization was facilitated by replacing ICL3 with a novel optimized variant of BRIL (OB1) that enhances the formation of intermolecular polar interactions, making OB1 a potential useful tool for structural studies of membrane proteins. Unlike the agonist ergotamine (ERG), MT occupies only the conserved orthosteric binding pocket, explaining the wide spectrum effect of MT on serotonin receptors. Compared with ERG, MT shifts toward TM6 and sterically pushes residues W3276.48, F3306.50 and F3316.51 from inside the orthosteric binding pocket, leading to an outward movement of the extracellular end and a corresponding inward shift of the intracellular end of TM6, a feature shared by other reported inactive G protein-coupled receptor (GPCR) structures. Together with the previous agonist-bound serotonin receptor structures, the inverse agonist-bound 5-HT1BR structure identifies a basis for the ligand-mediated switch of 5-HT1BR activity and provides a structural understanding of the inactivation mechanism of 5-HT1BR and some other class A GPCRs, characterized by ligand-induced outward movement of the extracellular end of TM6 that is coupled with inward movement of the cytoplasmic end of this helix.

Concepts: Signal transduction, Cell membrane, Receptor, Serotonin, Agonist, 5-HT receptor, 5-HT2C receptor, 5-HT1B receptor


Repeated episodes of binge-like alcohol consumption produce anxiety, depression and various deleterious effects including alterations in neurogenesis. While the involvement of the serotonin receptor 1 A (5-HT1A) in the regulation of anxiety-like behavior and neurogenesis is well documented, its contribution to alcohol withdrawal-induced anxiety and alcohol-induced deficits in neurogenesis is less documented. Using the Drinking-In-the-Dark (DID) paradigm to model chronic long-term (12 weeks) binge-like voluntary alcohol consumption in mice, we show that the selective partial activation of 5-HT1A receptors by tandospirone (3 mg/kg) prevents alcohol withdrawal-induced anxiety in a battery of behavioral tests (marble burying, elevated-plus-maze, open-field), which is accompanied by a robust decrease in binge-like ethanol intake (1 and 3 mg/kg). Furthermore, using triple immunolabelling of proliferation and neuronal differentiation markers, we show that long-term DID elicits profound deficits in neurogenesis and neuronal fate specification in the dorsal hippocampus that are entirely reversed by a 2-week chronic treatment with the 5-HT1A partial agonist tandospirone (3 mg/kg/day). Together, our results confirm previous observations that 5-HT1A receptors play a pivotal role in alcohol drinking behavior and the associated emotional and neurogenic impairments, and suggest that 5-HT1A partial agonists represent a promising treatment strategy for alcohol abuse.

Concepts: Psychology, Receptor antagonist, Serotonin, Agonist, Inverse agonist, Functional selectivity, 5-HT receptor, Buspirone


The prototypical hallucinogen LSD acts via serotonin receptors, and here we describe the crystal structure of LSD in complex with the human serotonin receptor 5-HT2B. The complex reveals conformational rearrangements to accommodate LSD, providing a structural explanation for the conformational selectivity of LSD’s key diethylamide moiety. LSD dissociates exceptionally slow from both 5-HT2BR and 5-HT2AR-a major target for its psychoactivity. Molecular dynamics (MD) simulations suggest that LSD’s slow binding kinetics may be due to a “lid” formed by extracellular loop 2 (EL2) at the entrance to the binding pocket. A mutation predicted to increase the mobility of this lid greatly accelerates LSD’s binding kinetics and selectively dampens LSD-mediated β-arrestin2 recruitment. This study thus reveals an unexpected binding mode of LSD; illuminates key features of its kinetics, stereochemistry, and signaling; and provides a molecular explanation for LSD’s actions at human serotonin receptors. PAPERCLIP.

Concepts: Signal transduction, Receptor, Serotonin, Agonist, 5-HT receptor, 5-HT2C receptor, 5-HT1A receptor, 5-HT2B receptor


Serotonin or 5-hydroxytryptamine (5-HT) regulates a wide spectrum of human physiology through the 5-HT receptor family. We report the crystal structures of the human 5-HT1B G protein-coupled receptor bound to the agonist antimigraine medications ergotamine and dihydroergotamine. The structures reveal similar binding modes for these ligands, which occupy the orthosteric pocket and an extended binding pocket close to the extracellular loops. The orthosteric pocket is formed by residues conserved in the 5-HT receptor family, clarifying the family-wide agonist activity of 5-HT. Compared with the accompanying structure of the 5-HT2B receptor, the 5-HT1B receptor displays a 3-angstrom outward shift at the extracellular end of helix V, resulting in a more open extended pocket that explains subtype selectivity. Together with docking and mutagenesis studies, these structures provide a comprehensive structural basis for understanding receptor-ligand interactions and designing subtype-selective serotonergic drugs.

Concepts: Signal transduction, Receptor, Serotonin, Agonist, 5-HT receptor, 5-HT2C receptor, 5-HT1B receptor, 5-HT2B receptor


The therapeutic effect of current antidepressant drugs appears after several weeks of treatment and a significant number of patients do not respond to treatment. Here, we report the effects of the multi-modal antidepressant vortioxetine (Lu AA21004), a 5-HT3 and 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and 5-HT transporter (SERT) inhibitor, on rat 5-HT neurotransmission. Using in vivo electrophysiological recordings in the dorsal raphe nucleus of anaesthetized rats, we assessed the acute and subchronic effects of vortioxetine and/or the selective 5-HT3 receptor agonist, SR57227 or the selective 5-HT1A receptor agonist flesinoxan, on 5-HT neuronal firing activity. Using ex-vivo autoradiography, we correlated SERT occupancy and presumed 5-HT firing activity. The selective serotonin reuptake inhibitor, fluoxetine, was used as comparator. Importantly, the recovery of 5-HT neuronal firing was achieved after 1 d with vortioxetine and 14 d with fluoxetine. SR57227 delayed this recovery. In contrast, vortioxetine failed to alter the reducing action of 3 d treatment of flesinoxan. Acute dosing of vortioxetine inhibited neuronal firing activity more potently than fluoxetine. SR57227 prevented the suppressant effect of vortioxetine, but not of fluoxetine. In contrast, flesinoxan failed to modify the suppressant effect of vortioxetine acutely administered. Differently to fluoxetine, vortioxetine suppressed neuronal firing without saturating occupancy at the SERT. Vortioxetine produced a markedly faster recovery of 5-HT neuronal firing than fluoxetine. This is at least partly due to 5-HT3 receptor antagonism of vortioxetine in association with its reduced SERT occupancy.

Concepts: Receptor antagonist, Serotonin, Agonist, Selective serotonin reuptake inhibitor, Inverse agonist, Buprenorphine, 5-HT receptor, Buspirone


The laryngeal chemoreflex (LCR), an airway protective reflex that causes apnea and bradycardia, has long been suspected as an initiating event in the sudden infant death syndrome (SIDS). Serotonin (5-HT) and 5-HT receptors may be deficient in the brainstems of babies who die of SIDS, and 5-HT seems to be important in terminating apneas directly or in causing arousals or as part of the process of autoresuscitation. We hypothesized that 5-HT in the brainstem would limit the duration of the LCR. We studied anesthetized rat pups between 7 and 21 days of age and made microinjections into the cisterna magna or into the nucleus of the solitary tract (NTS). Focal, bilateral microinjections of 5-HT into the caudal NTS significantly shortened the LCR. The 5-HT 1a receptor antagonist, WAY 100635, did not affect the LCR consistently, nor did a 5-HT2 receptor antagonist, ketanserin, alter the duration of the LCR. The 5-HT3 specific agonist, 1-(3-chlorophenyl)-biguanide, microinjected bilaterally into the caudal NTS significantly shortened the LCR. Thus, endogenous 5-HT released within the NTS may curtail the respiratory depression that is part of the LCR, and serotonergic shortening of the LCR may be attributed to activation of 5-HT3 receptors within the NTS. 5-HT3 receptors are expressed presynaptically on C-fiber afferents of the superior laryngeal nerve, and serotonergic shortening of the LCR may be mediated presynaptically by enhanced activation of inhibitory interneurons within the NTS that terminate during the LCR. This article is protected by copyright. All rights reserved.

Concepts: Receptor, Receptor antagonist, Serotonin, Agonist, Inverse agonist, Sudden infant death syndrome, 5-HT receptor, 5-HT2C receptor


RATIONALE: Venlafaxine is a non-selective serotonin and noradrenaline reuptake inhibitor antidepressant drug for which clinical studies have suggested a high level efficacy and a possible early action onset compared to the classical antidepressants. Its therapeutic effects might be due, at least in part, to adaptive changes in serotonergic neurotransmission, through the activation of the different 5-HT receptor subtypes. 5-HT1B receptors are located in the axon terminals of both serotonergic and non-serotonergic neurons, where they act as inhibitory autoreceptors or heteroreceptors, respectively. However, the information about the involvement of this subtype in the mechanism of action of antidepressants is limited and quite controversial. OBJECTIVES: The aim of this study was to evaluate the effect of venlafaxine (10 mg kg(-1) day(-1), p.o.) after 21 days of treatment on the density of 5-HT1B receptors and their functionality in rat brain. METHODS: Effects of chronic venlafaxine were evaluated at different levels of 5-HT1B receptor by using receptor autoradiography, [(35)S]GTPγS binding, and the regulation of body temperature induced by selective 5-HT1B agonist. RESULTS: Our results show that venlafaxine induced an increase in sensitivity of 5-HT1B receptors in hypothalamus both at G-protein level and the control of core temperature without affecting the receptor density. CONCLUSIONS: These results demonstrate that adaptive changes on 5-HT1B receptors induced by chronic administration of venlafaxine exhibit regional differences suggesting that the hypothalamus might be an important site of drug action.

Concepts: Action potential, Serotonin, Antidepressant, Selective serotonin reuptake inhibitor, Norepinephrine, Bupropion, Tricyclic antidepressant, 5-HT receptor


A novel series of arylpiperazinylalkyl 2-benzoxazolones and 2-benzothiazolones 18-38 was designed, synthesized and tested to evaluate their affinity for the 5-HT7 and 5-HT1A receptors. Compounds with a 2-benzothiazolone nucleus generally had affinity values higher than the corresponding 2-benzoxazolone compounds. In particular, derivatives possessing a six or seven carbon chain linker between 2-benzothiazolone and arylpiperazine had Ki values in the subnanomolar range for the 5-HT1A receptor and in the low nanomolar range for the 5-HT7 receptor, indicating that they may be interesting dual ligands. Molecular modeling studies revealed different docking poses for the investigated compounds in homology models of 5-HT1A and 5-HT7 receptors, which explained their experimentally determined affinities and general low selectivity. Additionally, structural interaction fingerprints analysis identified the important amino acid residues for the specific interactions of long-chain arylpiperazines within the binding pockets of both serotonin receptors.

Concepts: Protein, Amino acid, Receptor, Cell signaling, Serotonin, 5-HT receptor, Aripiprazole, 5-HT1A receptor


Uterine leiomyomas (fibroids or myomas) are the most common pelvic tumor in women with about 70% lifetime incidence rate. Currently, the only definitive treatment is surgery, causing undesirable side effects and negative impact on women’s quality of life, reproductive ability, and a substantial impact on healthcare costs. Therefore, curative medical treatments are needed to be developed. In this study, we investigated the impact of serotonin receptor 5-HT1B on cell proliferation and survival in human uterine leiomyoma cells (huLM).

Concepts: Medicine, Signal transduction, Cell division, Serotonin, Leiomyoma, Myometrium, 5-HT receptor, 5-HT1B receptor


Opioids may inhibit the serotonin and norepinephrine transporters (SERT and NET, respectively). NET inhibition may contribute to analgesia, and SERT inhibition or interactions with serotonin receptors may cause serotonergic toxicity. However, the effects of different opioids on the human SERT, NET, and serotonin receptors have not been sufficiently studied.

Concepts: Pharmacology, Serotonin, Inhibitor, Antidepressant, Norepinephrine, Pethidine, Tramadol, 5-HT receptor