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Pharmacology & Therapeutics Jun 2015Serotonin receptors are prevalent throughout the nervous system and the periphery, and remain one of the most lucrative and promising drug discovery targets for... (Review)
Review
Serotonin receptors are prevalent throughout the nervous system and the periphery, and remain one of the most lucrative and promising drug discovery targets for disorders ranging from migraine headaches to neuropsychiatric disorders such as schizophrenia and depression. There are 14 distinct serotonin receptors, of which 13 are G protein-coupled receptors (GPCRs), which are targets for approximately 40% of the approved medicines. Recent crystallographic and biochemical evidence has provided a converging understanding of the basic structure and functional mechanics of GPCR activation. Currently, two GPCR crystal structures exist for the serotonin family, the 5-HT1B and 5-HT2B receptor, with the antimigraine and valvulopathic drug ergotamine bound. The first serotonin crystal structures not only provide the first evidence of serotonin receptor topography but also provide mechanistic explanations into functional selectivity or biased agonism. This review will detail the findings of these crystal structures from a molecular and mutagenesis perspective for driving rational drug design for novel therapeutics incorporating biased signaling.
Topics: Allosteric Site; Animals; Ergotamine; GTP-Binding Proteins; Heart Valve Diseases; Humans; Migraine Disorders; Models, Molecular; Protein Conformation; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT2B; Receptors, Serotonin; Serotonin Receptor Agonists; Signal Transduction; Vasoconstrictor Agents
PubMed: 25601315
DOI: 10.1016/j.pharmthera.2015.01.009 -
Physiological Research 2011Serotonin (5-hydroxytryptamine) is an ubiquitary monoamine acting as one of the neurotransmitters at synapses of nerve cells. Serotonin acts through several receptor... (Review)
Review
Serotonin (5-hydroxytryptamine) is an ubiquitary monoamine acting as one of the neurotransmitters at synapses of nerve cells. Serotonin acts through several receptor types and subtypes. The profusion of 5-HT receptors should eventually allow a better understanding of the different and complex processes in which serotonin is involved. Its role is expected in the etiology of several diseases, including depression, schizophrenia, anxiety and panic disorders, migraine, hypertension, pulmonary hypertension, eating disorders, vomiting and irritable bowel syndromes. In the past 20 years, seven distinct families of 5-HT receptors have been identified and various subpopulations have been described for several of them. Increasing number of 5-HT receptors has made it difficult to unravel the role of 5-HT receptor subpopulations due to the lack of suitable selective agents. The present review describes the different populations and nomenclature of recently discovered 5-HT receptors and their pharmacological relevance.
Topics: Animals; Humans; Hypertension; Irritable Bowel Syndrome; Mental Disorders; Migraine Disorders; Receptors, Serotonin; Schizophrenia; Serotonin; Synaptic Transmission; Vomiting
PubMed: 20945968
DOI: 10.33549/physiolres.931903 -
Cell Jun 2023Serotonin influences many aspects of animal behavior. But how serotonin acts on its diverse receptors across the brain to modulate global activity and behavior is...
Serotonin influences many aspects of animal behavior. But how serotonin acts on its diverse receptors across the brain to modulate global activity and behavior is unknown. Here, we examine how serotonin release in C. elegans alters brain-wide activity to induce foraging behaviors, like slow locomotion and increased feeding. Comprehensive genetic analyses identify three core serotonin receptors (MOD-1, SER-4, and LGC-50) that induce slow locomotion upon serotonin release and others (SER-1, SER-5, and SER-7) that interact with them to modulate this behavior. SER-4 induces behavioral responses to sudden increases in serotonin release, whereas MOD-1 induces responses to persistent release. Whole-brain imaging reveals widespread serotonin-associated brain dynamics, spanning many behavioral networks. We map all sites of serotonin receptor expression in the connectome, which, together with synaptic connectivity, helps predict which neurons show serotonin-associated activity. These results reveal how serotonin acts at defined sites across a connectome to modulate brain-wide activity and behavior.
Topics: Animals; Caenorhabditis elegans; Serotonin; Caenorhabditis elegans Proteins; Receptors, Serotonin; Behavior, Animal; Brain
PubMed: 37192620
DOI: 10.1016/j.cell.2023.04.023 -
BMB Reports Oct 2023Serotonin receptors, also known as 5-HT receptors, belong to the G protein-coupled receptors (GPCRs) superfamily. They mediate the effects of serotonin, a... (Review)
Review
Serotonin receptors, also known as 5-HT receptors, belong to the G protein-coupled receptors (GPCRs) superfamily. They mediate the effects of serotonin, a neurotransmitter that plays a key role in a wide range of functions including mood regulation, cognition and appetite. The functions of serotonin are mediated by a family of 5-HT receptors including 12 GPCRs belonging to six major families: 5-HT, 5-HT, 5-HT, 5-HT, 5-HT and 5-HT. Despite their distinct characteristics and functions, these receptors' subtypes share common structural features and signaling mechanisms. Understanding the structure, functions and pharmacology of the serotonin receptor family is essential for unraveling the complexities of serotonin signaling and developing targeted therapeutics for neuropsychiatric disorders. However, developing drugs that selectively target specific receptor subtypes is challenging due to the structural similarities in their orthosteric binding sites. This review focuses on the recent advancements in the structural studies of 5-HT receptors, highlighting the key structural features of each subtype and shedding light on their potential as targets for mental health and neurological disorders (such as depression, anxiety, schizophrenia, and migraine) drugs. [BMB Reports 2023; 56(10): 527-536].
Topics: Serotonin; Receptors, Serotonin; Binding Sites
PubMed: 37817438
DOI: 10.5483/BMBRep.2023-0147 -
Biomolecules Dec 2021The present review summarizes the data concerning the influence of serotonin (5-HT) receptors on body temperature in warm-blooded animals and on processes associated... (Review)
Review
The present review summarizes the data concerning the influence of serotonin (5-HT) receptors on body temperature in warm-blooded animals and on processes associated with its maintenance. This review includes the most important part of investigations from the first studies to the latest ones. The established results on the pharmacological activation of 5-HT, 5-HT 5-HT and 5-HT receptor types are discussed. Such activation of the first 3 type of receptors causes a decrease in body temperature, whereas the 5-HT activation causes its increase. Physiological mechanisms leading to changes in body temperature as a result of 5-HT receptors' activation are discussed. In case of 5-HT receptor, they include an inhibition of shivering and non-shivering thermogenesis, as well simultaneous increase of peripheral blood flow, i.e., the processes of heat production and heat loss. The physiological processes mediated by 5-HT receptor are opposite to those of the 5-HT receptor. Mechanisms of 5-HT and 5-HT receptor participation in these processes are yet to be studied in more detail. Some facts indicating that in natural conditions, without pharmacological impact, these 5-HT receptors are important links in the system of temperature homeostasis, are also discussed.
Topics: Animals; Blood Circulation; Body Temperature; Homeostasis; Receptors, Serotonin; Thermogenesis
PubMed: 34944557
DOI: 10.3390/biom11121914 -
Theranostics 2021Serotonin or 5-hydroxytryptamine (5-HT) is a neurotransmitter known to affect emotion, behavior, and cognition, and its effects are mostly studied in neurological... (Review)
Review
Serotonin or 5-hydroxytryptamine (5-HT) is a neurotransmitter known to affect emotion, behavior, and cognition, and its effects are mostly studied in neurological diseases. The crosstalk between the immune cells and the nervous system through serotonin and its receptors (5-HTRs) in the tumor microenvironment and the secondary lymphoid organs are known to affect cancer pathogenesis. However, the molecular mechanism of - alteration in the phenotype and function of - innate and adaptive immune cells by serotonin is not well explored. In this review, we discuss how serotonin and serotonin receptors modulate the phenotype and function of various immune cells, and how the 5-HT-5-HTR axis modulates antitumor immunity. Understanding how 5-HT and immune signaling are involved in tumor immunity could help improve therapeutic strategies to control cancer progression and metastasis.
Topics: Adaptive Immunity; Animals; Humans; Immunity, Innate; Neoplasms; Receptors, Serotonin; Serotonin; Signal Transduction
PubMed: 33859748
DOI: 10.7150/thno.55986 -
Pharmacological Research Feb 2019Serotonin is a neurotransmitter widely conserved from ancient organisms lacking nervous systems through man, and its presence precedes the appearance of nervous systems... (Review)
Review
Serotonin is a neurotransmitter widely conserved from ancient organisms lacking nervous systems through man, and its presence precedes the appearance of nervous systems on both developmental and evolutionary time scales. Serotonin receptor subtypes diversified approximately at the time period during which vertebrates diverged from invertebrates. The biological and clinical importance of serotonin receptors, may benefit from studies on their evolution. Although potentially informative about their pathophysiological functions, reviews on this topic are sparse. Several observations support basic functions mediated by serotonin, both in periphery and central nervous system. In particular, 5-HT receptors have been implicated in embryonic development, including cell proliferation, survival, and/or differentiation, in either neural crest cell derivatives, myeloid cell lineage, or heart embryogenesis. In this review, we collected existing data about the genomic association between the RPN2 proteasome subunit gene Psmd1 and the 5-HT receptor gene Htr2b. We discuss about the possibility that, during genome duplications, a single copy of this pair of genes has been conserved, suggesting a strong selective pressure. Many basic physiological functions in which serotonin system is involved could be linked to the early association of these two genes in pre-vertebrates. Their evolutionary association highlights the possibility that the 5-HT receptor gene, Htr2b, is the common ancestor of 5-HT-receptor subfamily. Disentangling these possibilities could bring new understanding of the respective importance of these receptors in pathophysiology of serotonin.
Topics: Animals; Evolution, Molecular; Genomics; Humans; Proteasome Endopeptidase Complex; Receptors, Serotonin; Serotonin
PubMed: 30223085
DOI: 10.1016/j.phrs.2018.09.014 -
Current Drug Targets. CNS and... Feb 2004Serotonin 4 receptors (5-HT(4)Rs) were discovered 15 years ago. They are coded by a very complex gene (700Kb, 38 exons) which generates eight carboxy-terminal variants... (Review)
Review
Serotonin 4 receptors (5-HT(4)Rs) were discovered 15 years ago. They are coded by a very complex gene (700Kb, 38 exons) which generates eight carboxy-terminal variants (a, b, c, d, e, f, g, n). Their sequences differ after position L(358). Another variant is characterized by a 14 residue insertion within the extracellular loop 2. Highly selective potent 5-HT(4) receptor antagonists and partial agonists which cross the blood-brain barrier have been synthesized, but a specific full agonist for brain studies is still missing. Based on physiological and behavioral experiments, 5-HT(4)Rs may be targets to treat cognitive deficits, abdominal pain and feeding disorders. One 5-HT(4)R-directed drug (SL65.0155) is already in phase II to treat patients suffering from memory deficits or dementia.
Topics: Animals; Brain; Central Nervous System Diseases; Cloning, Molecular; Digestive System; Drug Evaluation; GTP-Binding Proteins; Gastrointestinal Diseases; Humans; Immunohistochemistry; Receptors, Serotonin, 5-HT4; Serotonin Antagonists; Serotonin Receptor Agonists; Signal Transduction; Structure-Activity Relationship; Tissue Distribution
PubMed: 14965243
DOI: 10.2174/1568007043482615 -
Cell Communication and Signaling : CCS Sep 2023Serotonin (5-hydroxytryptamine, 5-HT) is a unique neurotransmitter which can regulate various biological processes by activating thirteen different receptors. These... (Review)
Review
Serotonin (5-hydroxytryptamine, 5-HT) is a unique neurotransmitter which can regulate various biological processes by activating thirteen different receptors. These serotonin receptors are divided into seven different classes based on their structure and functions. Since these receptors co-express in various tissue and cell types and share the same ligand (5-HT), it has been a challenge for the researchers to define specific pathway and separate physiological role for each of these serotonin receptors. Though the evidence of operational diversity of these receptors is continuously emerging, much work remains to be done. 5-HTR1E is a member of 5-HT1 receptor family which belongs to G-protein coupled receptors (GPCRs). Even after three decades since its discovery, 5-HTR1E remains the least explored serotonin receptor. Very high similarity with another family member (5-HTR1F) and its non-existence in mice or rats makes 5-HTR1E a difficult target to study. Despite these challenges, recent findings on the role of 5-HTR1E in neuroprotection and diseases such as cancer, have excited many researchers to explore this receptor in detail. Here, we provide the first review of 5-HTR1E, since its discovery in 1989 to 2023. We highlight the structural and functional characteristics of this important serotonin receptor in detail and propose future directions in developing 5-HTR1E as a drug target. Video Abstract.
Topics: Animals; Mice; Rats; Serotonin; Receptors, Serotonin; Drug Delivery Systems
PubMed: 37723479
DOI: 10.1186/s12964-023-01195-0 -
Molecular Psychiatry Jun 2021Serotonin receptor 4 (5-HTR) plays an important role in regulating mood, anxiety, and cognition, and drugs that activate this receptor have fast-acting antidepressant...
Serotonin receptor 4 (5-HTR) plays an important role in regulating mood, anxiety, and cognition, and drugs that activate this receptor have fast-acting antidepressant (AD)-like effects in preclinical models. However, 5-HTR is widely expressed throughout the central nervous system (CNS) and periphery, making it difficult to pinpoint the cell types and circuits underlying its effects. Therefore, we generated a Cre-dependent 5-HTR knockout mouse line to dissect the function of 5-HTR in specific brain regions and cell types. We show that the loss of functional 5-HTR specifically from excitatory neurons of hippocampus led to robust AD-like behavioral responses and an elevation in baseline anxiety. 5-HTR was necessary to maintain the proper excitability of dentate gyrus (DG) granule cells and cell type-specific molecular profiling revealed a dysregulation of genes necessary for normal neural function and plasticity in cells lacking 5-HTR. These adaptations were accompanied by an increase in the number of immature neurons in ventral, but not dorsal, dentate gyrus, indicating a broad impact of 5-HTR loss on the local cellular environment. This study is the first to use conditional genetic targeting to demonstrate a direct role for hippocampal 5-HTR signaling in modulating mood and anxiety. Our findings also underscore the need for cell type-based approaches to elucidate the complex action of neuromodulatory systems on distinct neural circuits.
Topics: Animals; Anxiety; Dentate Gyrus; Hippocampus; Mice; Neurons; Receptors, Serotonin; Receptors, Serotonin, 5-HT4
PubMed: 33441982
DOI: 10.1038/s41380-020-00994-y