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Molecules (Basel, Switzerland) Jan 2023Serotonin receptors are involved in a number of physiological functions and regulate aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and...
Serotonin receptors are involved in a number of physiological functions and regulate aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and thermoregulation. Here we report synthesis and detailed structural and behavioral studies of three indole derivatives: D2AAK5, D2AAK6, and D2AAK7 as serotonin 5-HT and 5-HT receptor ligands. X-ray studies revealed that the D2AAK5 compound crystallizes in centrosymmetric triclinic space group with one molecule in the asymmetric unit. The main interaction between the ligands and the receptors is the salt bridge between the protonatable nitrogen atom of the ligands and the conserved Asp (3.32) of the receptors. The complexes were stable in the molecular dynamic simulations. MD revealed that the studied ligands are relatively stable in their binding sites, with the exception of D2AAK7 in the serotonin 5-HT receptor. D2AAK7 exerts anxiolytic activity in the EPM test, while D2AAK5 has a beneficial effect on the memory processes in the PA test.
Topics: Serotonin; Ligands; Receptor, Serotonin, 5-HT2A; Protein Binding; Receptors, Serotonin; Antipsychotic Agents; Receptor, Serotonin, 5-HT1A
PubMed: 36615578
DOI: 10.3390/molecules28010383 -
Neuron Jan 1996
Review
Topics: Aggression; Animals; Female; Gonadal Steroid Hormones; Humans; Impulsive Behavior; Male; Mammals; Maternal Behavior; Mice; Mice, Inbred Strains; Mice, Knockout; Mice, Transgenic; Monoamine Oxidase; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Violence
PubMed: 8562081
DOI: 10.1016/s0896-6273(00)80019-7 -
Molecular Cell Jul 2022Serotonin (or 5-hydroxytryptamine, 5-HT) is an important neurotransmitter that activates 12 different G protein-coupled receptors (GPCRs) through selective coupling of...
Serotonin (or 5-hydroxytryptamine, 5-HT) is an important neurotransmitter that activates 12 different G protein-coupled receptors (GPCRs) through selective coupling of G, G or G proteins. The structural basis for G protein subtype selectivity by these GPCRs remains elusive. Here, we report the structures of the serotonin receptors 5-HT, 5-HT, and 5-HT with G, and 5-HT with G. The structures reveal that transmembrane helices TM5 and TM6 alternate lengths as a macro-switch to determine receptor's selectivity for G and G, respectively. We find that the macro-switch by the TM5-TM6 length is shared by class A GPCR-G protein structures. Furthermore, we discover specific residues within TM5 and TM6 that function as micro-switches to form specific interactions with G or G. Together, these results present a common mechanism of G versus G protein coupling selectivity or promiscuity by class A GPCRs and extend the basis of ligand recognition at serotonin receptors.
Topics: GTP-Binding Proteins; Ligands; Receptors, G-Protein-Coupled; Receptors, Serotonin; Serotonin
PubMed: 35714614
DOI: 10.1016/j.molcel.2022.05.031 -
Behavioural Brain Research Apr 2021Serotonin signaling influences satiety and motivation through known actions in the hindbrain and hypothalamus. Recently, we reported that some classes of serotonin...
Serotonin signaling influences satiety and motivation through known actions in the hindbrain and hypothalamus. Recently, we reported that some classes of serotonin receptors also modulate food intake through actions in the ventral tegmentum and the nucleus accumbens. In the current experiments, we examined whether activation or blockade of individual serotonin receptor subtypes in the ventral tegmentum might also affect appetitive motivation for sugar pellets as assessed in a progressive ratio (PR) task. Separate groups of rats were tested following stimulation or blockade of ventral tegmental serotonin 1A, 1B, 2A, 2B, 2C, or 3 receptors. Rats within each group received multiple doses of a single drug across days; each test was separated by 72 h. Progressive ratio break point was significantly affected by stimulation of ventral tegmental serotonin 1A receptors with 8-OH-DPAT (0, 2, 4, 8 μg/side) or stimulation of serotonin 3 receptors with mCPBG (0, 10, & 20 μg/side). High doses of both agents tended to decrease break point. Additionally, stimulation of serotonin 2C receptors with RO60-0175 (at 0, 2, and 5 μg/side) reduced total lever presses and demonstrated a trend towards reducing break point. There were no effects of stimulating ventral tegmental serotonin 1B, 2A, or 2B receptors on break point; neither did antagonism of any of the serotonin receptor subtypes significantly affect performance. These data provide additional evidence that serotonergic signaling in the mesolimbic pathway affects motivated behavior, and demonstrate that a subset of serotonin receptors impact not only food consumption, but appetitive food-seeking as well.
Topics: Animals; Appetitive Behavior; Behavior, Animal; Dietary Sugars; Feeding Behavior; Motivation; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Reward; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Ventral Tegmental Area
PubMed: 33497748
DOI: 10.1016/j.bbr.2021.113139 -
European Journal of Medical Research Oct 2022Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social interaction and repetitive stereotyped behaviors. Previous studies...
BACKGROUND
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social interaction and repetitive stereotyped behaviors. Previous studies have reported an association of serotonin or 5-hydroxytryptamine (5-HT) with ASD, but the specific receptors and neurons by which serotonin modulates autistic behaviors have not been fully elucidated.
METHODS
RNAi-mediated knockdown was done to destroy the function of tryptophan hydroxylase (Trh) and all the five serotonin receptors. Given that ubiquitous knockdown of 5-HT2B showed significant defects in social behaviors, we applied the CRISPR/Cas9 system to knock out the 5-HT2B receptor gene. Social space assays and grooming assays were the major methods used to understand the role of serotonin and related specific receptors in autism-like behaviors of Drosophila melanogaster.
RESULTS
A close relationship was identified between serotonin and autism-like behaviors reflected by increased social space distance and high-frequency repetitive behavior in Drosophila. We further utilized the binary expression system to knock down all the five 5-HT receptors, and observed the 5-HT2B receptor as the main receptor responsible for the normal social space and repetitive behavior in Drosophila for the specific serotonin receptors underlying the regulation of these two behaviors. Our data also showed that neurons in the dorsal fan-shaped body (dFB), which expressed 5-HT2B, were functionally essential for the social behaviors of Drosophila.
CONCLUSIONS
Collectively, our data suggest that serotonin levels and the 5-HT2B receptor are closely related to the social interaction and repetitive behavior of Drosophila. Of all the 5 serotonin receptors, 5-HT2B receptor in dFB neurons is mainly responsible for serotonin-mediated regulation of autism-like behaviors.
Topics: Animals; Autism Spectrum Disorder; Autistic Disorder; Disease Models, Animal; Drosophila; Drosophila Proteins; Drosophila melanogaster; Neurons; Receptor, Serotonin, 5-HT2B; Receptors, Serotonin; Serotonin; Transcription Factors; Tryptophan Hydroxylase
PubMed: 36253869
DOI: 10.1186/s40001-022-00838-1 -
Pharmacology & Therapeutics Dec 2010This review focuses on new insights provided by gene-modified animals into the cardiovascular pharmacology of serotonin. During their development, mice mutant for... (Review)
Review
This review focuses on new insights provided by gene-modified animals into the cardiovascular pharmacology of serotonin. During their development, mice mutant for tryptophan hydroxylase 1 and lacking peripheral serotonin, or mutant for 5-HT(2B) receptors, display cardiac defects and dilated cardiomyopathy. The 5-HT(4) receptor is important for the maturation of cardiac conduction. In fact, transgenic approaches have revealed that adult cardiac status is strongly influenced by maternal serotonin. Serotonin has long been known to be a vasoconstrictor in adult physiology. Analysis of animals knocked-out for the serotonin transporter suggested a role in blood pressure control and revealed an effect of 5-HT(2B) receptor antagonists in hypertension. In the lung vasculature, mice lacking the 5-HT(2B) receptor gene that are exposed to chronic hypoxia are resistant to pulmonary hypertension, while 5-HT(1B) receptor and serotonin transporter mutant animals show partial resistance. In platelets, mutant mice revealed that serotonin transporter regulates not only the mechanisms by which serotonin is packaged and secreted but also platelet aggregation. Studies looking at adult cardiac remodeling showed that mice lacking the 5-HT(2B) receptor gene were protected from cardiac hypertrophy. Their fibroblasts were unable to secrete cytokines. Crossing these animals with mice overexpressing the receptor in cardiomyocytes revealed the contribution of cardiac fibroblasts and 5-HT(2B) receptors to cardiac hypertrophy. In mice lacking the monoamine oxidase-A gene, the role of serotonin degradation in cardiac hypertrophy was confirmed. Works with gene-modified animals has contributed strongly to the re-evaluation of the influence of serotonin on cardiovascular regulation, though several unknowns remain to be investigated.
Topics: Animals; Animals, Genetically Modified; Blood Platelets; Cardiovascular Abnormalities; Cardiovascular Agents; Cardiovascular Diseases; Heart; Hemostasis; Mice; Mice, Knockout; Rats; Rats, Mutant Strains; Receptor, Serotonin, 5-HT1B; Receptors, Serotonin; Serotonin
PubMed: 20828585
DOI: 10.1016/j.pharmthera.2010.08.004 -
Journal of Neurophysiology Mar 2015Sacrocaudal motoneuron gene expression is altered following a spinal transection. Of interest here is the regulation of serotonin (5-HT) receptors (R), glutamate...
Sacrocaudal motoneuron gene expression is altered following a spinal transection. Of interest here is the regulation of serotonin (5-HT) receptors (R), glutamate receptor, metabotropic 1 (mGluR1), and potassium-chloride cotransporter (KCC2), which mediate motoneuron excitability, locomotor recovery, and spasticity posttransection. The examination of these genes in lumbar motoneurons posttransection has not been studied, which is necessary for developing potential pharmacological interventions aimed at restoring locomotion and/or reducing spasticity. Also, if activity is to be used to promote recovery or reduce spasticity postinjury, a further examination of neuromuscular activity on gene expression posttransection is warranted. The purpose of this study was to examine motoneuronal gene expression of 5-HT receptors, KCC2, and mGluR1 at 3 mo following a complete thoracic spinal cord transection, with and without the inclusion of daily passive cycling. Physiological hindlimb extensor and flexor motoneurons were differentially identified with two retrograde fluorescent tracers, allowing for the identification and separate harvesting of extensor and flexor motoneurons with laser capture microdissection and the subsequent examination of mRNA content using quantitative RT-PCR analysis. We demonstrate that posttransection 5-HT1AR, 5-HT2CR, and mGluR1 expression was downregulated, whereas the 5-HT2AR was upregulated. These alterations in gene expression were observed in both flexor and extensor motoneurons, whereas passive cycling influenced gene expression in extensor but not flexor motoneurons. Passive cycling in extensor motoneurons further enhanced 5-HT2AR expression and increased 5-HT7R and KCC2 expression. Our results demonstrate that passive cycling influences serotonin receptor and KCC2 gene expression and that extensor motoneurons compared with flexor motoneurons may be more plastic to activity-based interventions posttransection.
Topics: Animals; Female; Hindlimb; Motor Neurons; Muscle, Skeletal; Physical Exertion; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Receptors, Serotonin; Symporters; K Cl- Cotransporters
PubMed: 25505109
DOI: 10.1152/jn.00550.2014 -
Scientific Reports Apr 2015G protein-coupled receptors (GPCRs) constitute a large family of receptor proteins that sense molecular signals on the exterior of a cell and activate signal...
G protein-coupled receptors (GPCRs) constitute a large family of receptor proteins that sense molecular signals on the exterior of a cell and activate signal transduction pathways within the cell. Modeling how an agonist activates such a receptor is fundamental for an understanding of a wide variety of physiological processes and it is of tremendous value for pharmacology and drug design. Inelastic electron tunneling spectroscopy (IETS) has been proposed as a model for the mechanism by which olfactory GPCRs are activated by a bound agonist. We apply this hyothesis to GPCRs within the mammalian nervous system using quantum chemical modeling. We found that non-endogenous agonists of the serotonin receptor share a particular IET spectral aspect both amongst each other and with the serotonin molecule: a peak whose intensity scales with the known agonist potencies. We propose an experiential validation of this model by utilizing lysergic acid dimethylamide (DAM-57), an ergot derivative, and its deuterated isotopologues; we also provide theoretical predictions for comparison to experiment. If validated our theory may provide new avenues for guided drug design and elevate methods of in silico potency/activity prediction.
Topics: Cell Line; Doxorubicin; Drug Design; Electrons; Humans; Lysergic Acid Diethylamide; Models, Chemical; Quantum Theory; Receptors, Serotonin; Serotonin Receptor Agonists; Signal Transduction
PubMed: 25909758
DOI: 10.1038/srep09990 -
Scientific Reports Sep 2016Serotonin is important in brain functions and involved in neurological diseases. It is also drawn considerable attention in bone disease since it mainly produced by the...
Serotonin is important in brain functions and involved in neurological diseases. It is also drawn considerable attention in bone disease since it mainly produced by the gut. Serotonin 6 G-protein-coupled receptor (5-HT6R) is clinical targets for the treatment of neurological diseases. However, 5-HT6R as a therapeutic target in bone has not been reported. Herein, we found that 5-HT6R showed higher expression in bone, and its expression was increased during bone remodeling and osteoblast differentiation. The activation of 5-HT6R by ST1936 caused the inhibition of ALP activity and mineralization in primary osteoblast cultures, which was antagonized by SB258585, an antagonist and by the knockdown of 5-HT6R. Further investigation indicated that 5-HT6R inhibited osteoblast differentiation via Jab1 in BMP2 signaling but not PKA and ERK1/2. In vivo studies showed that the activation of 5-HT6R inhibited bone regeneration in the calvarial defect mice and also delayed bone development in newborn mice; this response was antagonized by SB258585. Therefore, our findings indicate a key role of 5-HT6R in bone formation through serotonin originating in the peripheral system, and suggest that it is a novel therapeutic target for drug development in the bone repair and bone diseases.
Topics: Animals; Bone Development; Bone Regeneration; Cell Differentiation; Cells, Cultured; Female; Mice; Mice, Inbred ICR; Receptors, Serotonin; Serotonin; Serotonin Receptor Agonists; Signal Transduction; Skull
PubMed: 27581523
DOI: 10.1038/srep30985 -
Journal of Neurochemistry Jul 2022Serotonergic psychedelics are substances that induce alterations in mood, perception, and thought, and have the activation of serotonin (5-HT) 2A receptors (5-HT Rs) as... (Review)
Review
Serotonergic psychedelics are substances that induce alterations in mood, perception, and thought, and have the activation of serotonin (5-HT) 2A receptors (5-HT Rs) as a main pharmacological mechanism. Besides their appearance on the (illicit) drug market, e.g. as new psychoactive substances, their potential therapeutic application is increasingly explored. This group of substances demonstrates a broad structural variety, leading to insufficiently described structure-activity relationships, hence illustrating the need for better functional characterization. This review therefore elaborates on the in vitro molecular techniques that have been used the most abundantly for the characterization of (psychedelic) 5-HT R agonists. More specifically, this review covers assays to monitor the canonical G protein signaling pathway (e.g. measuring G protein recruitment/activation, inositol phosphate accumulation, or Ca mobilization), assays to monitor non-canonical G protein signaling (such as arachidonic acid release), assays to monitor β-arrestin recruitment or signaling, and assays to monitor receptor conformational changes. In particular, focus lies on the mechanism behind the techniques, and the specific advantages and challenges that are associated with these. Additionally, several variables are discussed that one should consider when attempting to compare functional outcomes from different studies, both linked to the specific assay mechanism and linked to its specific execution, as these may heavily impact the assay outcome.
Topics: Central Nervous System Agents; Hallucinogens; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Serotonin; Serotonin 5-HT2 Receptor Agonists
PubMed: 34978711
DOI: 10.1111/jnc.15570