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International Journal of Clinical... Sep 2007In the 1960s, serotonin (5HT) was associated with pulmonary arterial hypertension (PAH) caused by certain diet pills, but has recently been the subject of renewed... (Review)
Review
In the 1960s, serotonin (5HT) was associated with pulmonary arterial hypertension (PAH) caused by certain diet pills, but has recently been the subject of renewed interest in the field of PAH. Serotonin can be synthesised in the pulmonary endothelium with the rate-limiting step being the activity of tryptophan hydroxylase1 (Tph1). The serotonin is released and can then: (i) pass into the underlying pulmonary smooth muscle cells through the serotonin transporter (SERT) to initiate proliferation and/or (ii) activate serotonin receptors on pulmonary smooth muscle cells to evoke proliferation and/or contraction. Serotonin may also mediate pulmonary fibroblast proliferation via the SERT and/or serotonin receptors. Here we will unravel, discuss and update the 'serotonin hypothesis' of PAH in light of recent advances in the field. In conclusion, the activity of serotonin receptors, the SERT and Tph1 can all be elevated in clinical and experimental PAH and each offers a potentially unique therapeutic target.
Topics: Dexfenfluramine; Humans; Hypertension, Pulmonary; Potassium Channels; Receptors, Serotonin; Serotonin; Serotonin Plasma Membrane Transport Proteins; Serotonin Receptor Agonists; Tryptophan Hydroxylase
PubMed: 17663674
DOI: 10.1111/j.1742-1241.2007.01497.x -
British Journal of Pharmacology Jan 2006This review outlines the history of our knowledge of the neuropharmacology of 5-hydroxytryptamine (5-HT; serotonin), focusing primarily on the work of U.K. scientists....
This review outlines the history of our knowledge of the neuropharmacology of 5-hydroxytryptamine (5-HT; serotonin), focusing primarily on the work of U.K. scientists. The existence of a vasoconstrictive substance in the blood has been known for over 135 years. The substance was named serotonin and finally identified as 5-HT in 1949. The presence of 5-HT in the brain was reported by Gaddum in 1954 and it was Gaddum who also demonstrated that the action of 5-HT (in the gut) was antagonised by the potent hallucinogen lysergic acid diethylamide. This provoked the notion that 5-HT played a pivotal role in the control of mood and subsequent investigations have generally confirmed this hypothesis. Over the last 50 years a good understanding has been gained of the mechanisms involved in control of the storage, synthesis and degradation of 5-HT in the brain. Knowledge has also been gained on control of the functional activity of this monoamine, often by the use of behavioural models. A considerable literature also now exists on the mechanisms by which many of the drugs used to treat psychiatric illness alter the functional activity of 5-HT, particularly the drugs used to treat depression. Over the last 20 years the number of identified 5-HT receptor subtypes has increased from 2 to 14, or possibly more. A major challenge now is to utilise this knowledge to develop receptor-specific drugs and use the information gained to better treat central nervous system disorders.
Topics: Animals; Antidepressive Agents; Brain; History, 20th Century; History, 21st Century; Humans; Receptors, Serotonin; Serotonin; Serotonin Agents; United Kingdom
PubMed: 16402098
DOI: 10.1038/sj.bjp.0706427 -
The Journal of Headache and Pain Dec 2009After the triptans, a calcitonin gene-related peptide blocker (telcagepant) is the first acute medicine that has been developed primarily for treatment of acute... (Review)
Review
After the triptans, a calcitonin gene-related peptide blocker (telcagepant) is the first acute medicine that has been developed primarily for treatment of acute migraine. Otherwise, the new drugs have been developed first for other purposes, like anticonvulsants, antihypertensives and antidepressants used for migraine prophylaxis. For acute attacks, a new way to administer a traditional drug like dihydroergotamine is under way, and documentation of efficacy in migraine has been gained for some commonly used painkillers and anti-inflammatory drugs, and for some herbal extracts. Based on insights into the basic pathophysiological mechanisms of the disorder, some drugs have been developed which seem promising in early phase II studies (NOS inhibitors and 5HT1F-receptor agonists). In the future, development and enhancements of existing medicines must be accompanied by increased efforts to develop truly new migraine drugs based on knowledge of the pathophysiology if one wishes to reduce substantially the great burden migraine poses on patients and society.
Topics: Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Clinical Trials as Topic; Drug Design; Drug Evaluation, Preclinical; Enzyme Inhibitors; Humans; Imidazoles; Migraine Disorders; Nitric Oxide Synthase; Receptors, Calcitonin Gene-Related Peptide; Receptors, Serotonin; Serotonin Receptor Agonists; Receptor, Serotonin, 5-HT1F
PubMed: 19795182
DOI: 10.1007/s10194-009-0156-9 -
Biochemical and Biophysical Research... Sep 2022Serotonin (5-hydroxytryptamine, 5-HT) and its receptors play important roles in the development and progression of malignant tumors. The effect of the 5-HT receptor 1D...
Serotonin (5-hydroxytryptamine, 5-HT) and its receptors play important roles in the development and progression of malignant tumors. The effect of the 5-HT receptor 1D (HTR1D), a member of the serotonin receptor family, on gastric cancer (GC) is not clear. Analysis of clinical data has shown that high expression of HTR1D was associated with poor prognosis in patients with GC and was an independent risk factor for reduced overall survival (OS) and disease-free survival (DFS). The present study assessed the effects of HTR1D knockdown and the HTR1D inhibitor GR127935 on the biological behavior of GC cells, which both impaired the proliferation and migration of GC cells. RNA sequencing showed that GR127935 inhibited tumor progression by limiting DNA replication and the cell cycle, inducing ferroptosis, and affecting tumor metabolism. Taken together, these findings showed that HTR1D has a potent oncogenic effect on GC and may provide a novel therapeutic target.
Topics: Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Serotonin; Serotonin 5-HT1 Receptor Antagonists; Stomach Neoplasms
PubMed: 35785570
DOI: 10.1016/j.bbrc.2022.06.088 -
Current Medicinal Chemistry 2018Geissoschizine methyl ether (GM) is one of the indole alkaloids in Uncaria hook, and an active ingredient of yokukansan (YKS) that improves behavioral and psychological... (Review)
Review
BACKGROUND
Geissoschizine methyl ether (GM) is one of the indole alkaloids in Uncaria hook, and an active ingredient of yokukansan (YKS) that improves behavioral and psychological symptoms of dementia (BPSD) in patients with several types of dementia. The pharmacological action of GM has been related to various serotonin (5-HT) receptor subtypes.
OBJECTIVE
The aim of this article is to review the binding characteristics of GM to the 5-HT receptor subtypes in the brains using our own data and previous findings.
METHOD
Competitive receptor-binding and agonist/antagonist activity assays for several 5-HT receptor subtypes were performed. Moreover, the articles describing pharmacokinetics and brain distribution of GM were searched in PubMed.
RESULTS
GM bound the following 5-HT receptor subtypes: 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5- HT4, 5-HT5A, 5-HT6, and 5-HT7. Among these receptors, GM had partial agonistic activity for 5-HT1A receptors and antagonistic activity for 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors. Also, GM was metabolized by various CYP isoforms, mainly CYP3A4. Parent/unchanged GM was detected in both the blood and brain of rats after oral administration of YKS. In the brains, GM was presumed to bind to 5- HT1A, 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors on neuron-like large cells mainly in the frontal cortex.
CONCLUSION
These results suggest that GM is a pharmacologically important alkaloid that regulates various serotonergic activities or functions by binding to multiple 5-HT receptor subtypes. Thus, this review provides recent 5-HT receptor-related evidence that GM is partly responsible for pharmacological effects of YKS.
Topics: Animals; Binding, Competitive; Brain; Drugs, Chinese Herbal; Humans; Indole Alkaloids; Protein Binding; Rats; Receptors, Serotonin; Uncaria
PubMed: 28322152
DOI: 10.2174/0929867324666170320114713 -
Neuroscience Sep 2011Learning and memory in the fruit fly, Drosophila melanogaster, is a complex behavior with many parallels to mammalian learning and memory. Although many...
Learning and memory in the fruit fly, Drosophila melanogaster, is a complex behavior with many parallels to mammalian learning and memory. Although many neurotransmitters including acetylcholine, dopamine, glutamate, and GABA have previously been demonstrated to be involved in aversive olfactory learning and memory, the role of serotonin has not been well defined. Here, we present the first evidence of the involvement of individual serotonin receptors in olfactory learning and memory in the fly. We initially followed a pharmacological approach, utilizing serotonin receptor agonists and antagonists to demonstrate that all serotonin receptor families present in the fly are necessary for short-term learning and memory. Isobolographic analysis utilizing combinations of drugs revealed functional interactions are occurring between 5-HT(1A)-like and 5-HT(2), and 5-HT(2) and 5-HT(7) receptor circuits in mediating short-term learning and memory. Examination of long-term memory suggests that 5-HT(1A)-like receptors are necessary for consolidation and important for recall, 5-HT(2) receptors are important for consolidation and recall, and 5-HT(7) receptors are involved in all three phases. Importantly, we have validated our pharmacological results with genetic experiments and showed that hypomorph strains for 5-HT(2)Dro and 5-HT(1B)Dro receptors, as well as knockdown of 5-HT(7)Dro mRNA, significantly impair performance in short-term memory. Our data highlight the importance of the serotonin system and individual serotonin receptors to influence olfactory learning and memory in the fly, and position the fly as a model system to study the role of serotonin in cognitive processes relevant to mammalian CNS function.
Topics: Animals; Brain; Conditioning, Classical; Drosophila melanogaster; Female; Learning; Male; Memory; Receptors, Serotonin; Smell
PubMed: 21749913
DOI: 10.1016/j.neuroscience.2011.06.058 -
The Journal of Physiology Jan 2009The attenuation of food intake as induced by an increase in serotonergic (5-hydroxytryptamine, 5-HT) efficacy has been a target of antiobesity pharmacotherapies.... (Review)
Review
The attenuation of food intake as induced by an increase in serotonergic (5-hydroxytryptamine, 5-HT) efficacy has been a target of antiobesity pharmacotherapies. However, the induction of tolerance and/or side-effects limited the clinical utility of the earliest serotonin-related medications. With the global prevalence of obesity rising, there has been renewed interest in the manipulation of the serotonergic system as a point of pharmacological intervention. The serotonin(2C) receptor (5-HT(2C)R), serotonin(1B) (rodent)/serotonin(1Dbeta) (human) receptor (5-HT(1B/1Dbeta)R) and serotonin(6) receptor (5-HT(6)R) represent the most promising serotonin receptor therapeutic targets. Canonical serotonin receptor compounds have given way to a myriad of novel receptor-selective ligands, many of which have observable anorectic effects. Here we review serotonergic compounds reducing ingestive behaviour and discuss their clinical potential for the treatment of obesity.
Topics: Animals; Appetite Regulation; Eating; Fenfluramine; Humans; Hypothalamus; Mice; Mice, Knockout; Models, Neurological; Obesity; Receptors, Serotonin; Serotonin; Serotonin Agents
PubMed: 19029184
DOI: 10.1113/jphysiol.2008.164152 -
CNS Neuroscience & Therapeutics Jul 2014Serotonin (5-hydroxytryptamine or 5-HT) is an important neurotransmitter regulating a wide range of physiological and pathological functions via activation of... (Review)
Review
Serotonin (5-hydroxytryptamine or 5-HT) is an important neurotransmitter regulating a wide range of physiological and pathological functions via activation of heterogeneously expressed 5-HT receptors. Besides the important role of 5-HT receptors in the pathogenesis of depressive disorders and in their clinical medications, underlying mechanisms are far from being completely understood. This review focuses on possible cross talk between two serotonin receptors, 5-HT1A and the 5-HT7 . Although these receptors are highly co-expressed in brain regions implicated in depression, and most agonists developed for the 5-HT1A or 5-HT7 receptors have cross-reactivity, their functional interaction has not been yet established. It has been recently shown that 5-HT1A and 5-HT7 receptors form homo- and heterodimers both in vitro and in vivo. From the functional point of view, heterodimerization has been shown to play an important role in regulation of receptor-mediated signaling and internalization, suggesting the implication of heterodimerization in the development and maintenance of depression. Interaction between these receptors is also of clinical interest, because both receptors represent an important pharmacological target for the treatment of depression and anxiety.
Topics: Animals; Brain; Depressive Disorder; Humans; Protein Multimerization; Receptor Cross-Talk; Receptor, Serotonin, 5-HT1A; Receptors, Serotonin; Signal Transduction
PubMed: 24935787
DOI: 10.1111/cns.12247 -
Experimental Brain Research Oct 2013The original model of G-protein activation by a single G-protein-coupled receptor (GPCR) is giving way to a new model, wherein two protomers of a GPCR dimer interact... (Review)
Review
The original model of G-protein activation by a single G-protein-coupled receptor (GPCR) is giving way to a new model, wherein two protomers of a GPCR dimer interact with a single G-protein. This article will review the evidence suggesting that 5-HT receptors form dimers/oligomers and will compare the findings with the results obtained from the studies with other biogenic amine receptors. Topics to be covered include the origin or biogenesis of dimer formation, potential dimer interface(s), and oligomer size (dimer vs. tetramer or higher order). The functional significance will be discussed in terms of G-protein activation following ligand binding to one or two protomers in a dimeric structure, the formation of heterodimers, and the development of bivalent ligands.
Topics: Animals; Enzyme Activation; Humans; Ligands; Protein Multimerization; Receptors, Serotonin; Serotonin
PubMed: 23811735
DOI: 10.1007/s00221-013-3622-1 -
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