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Cellular and Molecular Gastroenterology... 2021Serotonin signaling is ubiquitous in the gastrointestinal (GI) system, where it acts as a neurotransmitter in the enteric nervous system (ENS) and influences intestinal... (Review)
Review
Serotonin signaling is ubiquitous in the gastrointestinal (GI) system, where it acts as a neurotransmitter in the enteric nervous system (ENS) and influences intestinal motility and inflammation. Since its discovery, serotonin has been linked to cellular proliferation in several types of tissues, including vascular smooth muscle, neurons, and hepatocytes. Activation of serotonin receptors on distinct cell types has been shown to induce well-known intracellular proliferation pathways. In the GI tract, potentiation of serotonin signaling results in enhanced intestinal epithelial proliferation, and decreased injury from intestinal inflammation. Furthermore, activation of the type 4 serotonin receptor on enteric neurons leads to neurogenesis and neuroprotection in the setting of intestinal injury. It is not surprising that the mitogenic properties of serotonin are pronounced within the GI tract, where enterochromaffin cells in the intestinal epithelium produce 90% of the body's serotonin; however, these proliferative effects are attributed to increased serotonin signaling within the ENS compartment as opposed to the intestinal mucosa, which are functionally and chemically separate by virtue of the distinct tryptophan hydroxylase enzyme isoforms involved in serotonin synthesis. The exact mechanism by which serotonergic neurons in the ENS lead to intestinal proliferation are not known, but the activation of muscarinic receptors on intestinal crypt cells indicate that cholinergic signaling is essential to this signaling pathway. Further understanding of serotonin's role in mucosal and enteric nervous system mitogenesis may aid in harnessing serotonin signaling for therapeutic benefit in many GI diseases, including inflammatory bowel disease, malabsorptive conditions, and cancer.
Topics: Animals; Cell Proliferation; Cell Survival; Gastrointestinal Motility; Gastrointestinal Tract; Humans; Mitogens; Receptors, Serotonin; Serotonin; Signal Transduction
PubMed: 34022423
DOI: 10.1016/j.jcmgh.2021.05.008 -
The Neuroscientist : a Review Journal... Dec 2012N-Acetylserotonin (NAS) is a naturally occurring chemical intermediate in biosynthesis of melatonin. Previous studies have shown that NAS has different brain... (Review)
Review
N-Acetylserotonin (NAS) is a naturally occurring chemical intermediate in biosynthesis of melatonin. Previous studies have shown that NAS has different brain distribution patterns from those of serotonin and melatonin, suggesting that NAS might have functions other than as a precursor or metabolite of melatonin. Indeed, several studies have now shown that NAS may play an important role in mood regulation and may have antidepressant activity. Additional studies have shown that NAS stimulates proliferation of neuroprogenitor cells and prevents some of the negative effects of sleep deprivation. It is believed that the antidepressant and neurotrophic actions of NAS are due at least in part to the capability on this molecule to activate the TrkB receptor in a brain-derived neurotrophic factor-independent manner. Emerging evidence also indicates that NAS and its derivatives have neuroprotective properties and protect retinal photoreceptor cells from light-induced degeneration. In this review, the authors discuss the literature about this exciting and underappreciated molecule.
Topics: Animals; Brain; Humans; Neurogenesis; Neuroprotective Agents; Serotonin; Sleep
PubMed: 22585341
DOI: 10.1177/1073858412446634 -
FEBS Letters Jul 2015Metabolic homeostasis in the organism is assured both by the nervous system and by hormones. Among a plethora of hormones regulating metabolism, serotonin presents a... (Review)
Review
Metabolic homeostasis in the organism is assured both by the nervous system and by hormones. Among a plethora of hormones regulating metabolism, serotonin presents a number of unique features. Unlike classical hormones serotonin is produced in different anatomical locations. In brain it acts as a neurotransmitter and in the periphery it can act as a hormone, auto- and/or paracrine factor, or intracellular signaling molecule. Serotonin does not cross the blood-brain barrier; therefore the two major pools of this bioamine remain separated. Although 95% of serotonin is produced in the periphery, its functions have been ignored until recently. Here we review the impact of the peripheral serotonin on the regulation of function of the organs involved in glucose and lipid homeostasis.
Topics: Adipose Tissue; Animals; Energy Metabolism; Gluconeogenesis; Glucose; Hepatocytes; Homeostasis; Humans; Immune System; Islets of Langerhans; Metabolic Diseases; Serotonin
PubMed: 26070423
DOI: 10.1016/j.febslet.2015.05.054 -
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 -
Current Drug Targets May 2013This mini-review focuses on the studies of late Prof. IP Lapin (1903 - 2012) and his research team on the role of methoxyindole and kynurenine (KYN) pathways of... (Review)
Review
This mini-review focuses on the studies of late Prof. IP Lapin (1903 - 2012) and his research team on the role of methoxyindole and kynurenine (KYN) pathways of tryptophan (TRP) metabolism in the pathogenesis of depression and action mechanisms of antidepressant effect. In the late 60s of the last century Prof. IP Lapin suggested that "intensification of central serotoninergic processes is a determinant of the thymoleptic (mood elevating) component" while "activation of noradrenergic processes is responsible for psychoenergetic and motor-stimulating component of the clinical antidepressant effect". The cause of serotonin deficiency in depression was attributed to the shunt of TRP "metabolism away from serotonin production towards KYN production" due to cortisol-induced activation of liver enzyme, tryptophan 2,3- dioxygenase, the rate-limiting enzyme of TRP - KYN pathway. Prof. Lapin suggested and discovered that KYN and its metabolites affect brain functions, and proposed the role of neurokynurenines in pathogenesis of depression and action mechanisms of antidepressant effect (kynurenine hypothesis). Further research suggested the antidepressant and cognition- enhancing effects of post-serotonin metabolite, N-acetylserotonin (NAS), an agonist to tyrosine kinase B (TrkB) receptor; and link between depression and chronic inflammation-associated disorders (e.g., insulin resistance, hepatitis C virus) via inflammation-induced activation of indoleamine 2,3- dioxygenase, brain located rate-limiting enzyme of TRY - KYN metabolism. NAS and kynurenines might be the targets for prevention and treatment of depression and associated conditions.
Topics: Animals; Antidepressive Agents; Brain; Cognition; Depression; Drug Design; Emotions; History, 20th Century; History, 21st Century; Humans; Kynurenine; Serotonin; Signal Transduction
PubMed: 23514379
DOI: 10.2174/1389450111314050002 -
ACS Chemical Neuroscience May 2017Serotonin, or 5-hydroxytryptamine (5HT), is an important neurotransmitter in the nervous system of both vertebrates and invertebrates. Deficits in 5HT signaling are...
Serotonin, or 5-hydroxytryptamine (5HT), is an important neurotransmitter in the nervous system of both vertebrates and invertebrates. Deficits in 5HT signaling are responsible for many disabling psychiatric conditions, and its molecular machinery is the target of many pharmaceuticals. We present a new 5HT phototrigger, the compound [Ru(bpy)(PMe)(5HT)], where PMe is trimethylphosphine. As with other ruthenium-bipyridyl based caged compounds, [Ru(bpy)(PMe)(5HT)] presents activity in the visible region of the spectrum. We characterize and discuss the photochemical properties of the caged compound, and demonstrate its use by modulating the excitability of mouse prefrontal principal neurons.
Topics: Animals; Light; Mice; Neurons; Prefrontal Cortex; Ruthenium; Serotonin
PubMed: 28460173
DOI: 10.1021/acschemneuro.7b00083 -
Vascular Pharmacology Oct 2014Blood pressure regulation by 5-HT has proven to be a complex story to unravel. The work by Cuesta et al., in this issue of Vascular Pharmacology adds another layer of... (Review)
Review
Blood pressure regulation by 5-HT has proven to be a complex story to unravel. The work by Cuesta et al., in this issue of Vascular Pharmacology adds another layer of complexity by providing sound in vivo data that 5-HT, through the 5-HT7 receptor, can inhibit the vasodepressor actions of the sensory nervous system and thereby promote blood pressure maintenance. This interaction of 5-HT with the sensory nervous system is inhibitory, whereas 5-HT is understood to be stimulatory in other systems. Moreover, activation of the 5-HT7 receptor has been linked to both reduction and elevation of blood pressure. These interactions are discussed in this mini-review, as are potential steps forward in understanding the interplay of 5-HT, the sensory nervous system and blood pressure.
Topics: Blood Pressure; Humans; Receptors, Serotonin; Serotonin
PubMed: 25181552
DOI: 10.1016/j.vph.2014.08.003 -
International Journal of Molecular... May 2022The 5-HT2A serotonin receptor (HTR2A) has been reported to be involved in the serotonin- or serotonin receptor 2A agonist-induced melanogenesis in human melanoma cells....
The 5-HT2A serotonin receptor (HTR2A) has been reported to be involved in the serotonin- or serotonin receptor 2A agonist-induced melanogenesis in human melanoma cells. However, the molecular mechanisms underlying HTR2A in regulating melanogenesis remain poorly understood. In this research, cultured mouse melanoma cell line B16F10, human skin, and zebrafish embryos were used to elucidate the downstream signaling of HTR2A in regulating melanogenesis and to verify the potential application of HTR2A in the treatment of pigment-associated cutaneous diseases. We demonstrated that HTR2A antagonists (AT1015 and ketanserin) attenuated the melanogenesis induction of serotonin in both mouse melanoma cells and zebrafish embryos. The agonists of HTR2A (DOI and TCB-2) increased melanin synthesis and transfer in B16F10 cells, human skin tissue, and zebrafish embryos. Furthermore, the HTR2A agonists increased the expression of proteins related to melanosome organization and melanocyte dendrites to facilitate the melanocyte migration and melanosome transport. HTR2A antagonists and genetic knockout of zebrafish (the homologue of mammalian gene) were also used to clarify that HTR2A mediates serotonin and DOI in regulating melanogenesis. Finally, through small scale screening of the candidate downstream pathway, we demonstrated that HTR2A mediates the melanogenesis induction of its ligands by activating the PKA/CREB signaling pathway. In this research, we further confirmed that HTR2A is a crucial protein to mediate melanocyte function. Meanwhile, this research supports that HTR2A could be designed as a drug target for the development of chemicals to treat cutaneous diseases with melanocytes or melanogenesis abnormality.
Topics: Animals; Cell Line, Tumor; Mammals; Melanins; Melanocytes; Melanoma; Mice; Serotonin; Signal Transduction; Zebrafish
PubMed: 35682806
DOI: 10.3390/ijms23116111 -
Pharmacology, Biochemistry, and Behavior Oct 2021Serotonin (5-HT) is known to play a critical role in regulation of essential neural processes, whereas more recent research highlights serotonin's modulatory effects on... (Review)
Review
Serotonin (5-HT) is known to play a critical role in regulation of essential neural processes, whereas more recent research highlights serotonin's modulatory effects on cognition and executive functioning. Current examinations have identified specific serotonin receptors for their direct impact on behavioral flexibility. Providing definitive evidence for the impact of specific receptor targets on behavioral flexibility is difficult, due to the range of behavioral tests used. Due to limited studies and the sheer amount of different serotonin receptor targets, beginning to bring these studies together is important for the field. Our current review of the literature aims to differentiate how modulation of specific 5-HT receptors affects behavioral flexibility. Although more studies have examined 5-HT, 5-HT, and 5-HT receptors, it is unclear why this is the case. Above all, there are some paradoxical results pertaining to these receptor targets. There is a clear distinction between 5-HT and 5-HT, which conveys that these two receptor subtypes have inverse effects when compared to each other. In addition, some findings support one another, such as upregulation of 5-HT receptors impairs flexibility, while blockade alleviates this impairment in both drug-induced and disease model rodent studies. Further understanding how modulatory effects of specific 5-HT receptors impact behavioral flexibility is imperative to advance the development of new therapeutics for neuropsychiatric disorders afflicted by behavioral inflexibility.
Topics: Animals; Behavior, Animal; Cognition; Executive Function; Female; Humans; Male; Mice; Rats; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Reversal Learning; Serotonin
PubMed: 34314738
DOI: 10.1016/j.pbb.2021.173243 -
Pharmacological Reports : PR 2013This review contains background information on the serotonin system, furthermore the suggestion to introduce the term Contemporary Witness Report (CWR) for a novel type... (Review)
Review
Serotonin discovery and stepwise disclosure of 5-HT receptor complexity over four decades. Part I. General background and discovery of serotonin as a basis for 5-HT receptor identification.
This review contains background information on the serotonin system, furthermore the suggestion to introduce the term Contemporary Witness Report (CWR) for a novel type of review and, as the main part, an overview over the history of serotonin discovery as a basis for the identification of its receptor heterogeneity and the increase in complexity by genetic and allosteric variation. The present article conforms to CWRs in historical and autobiographical elements, in more emphasis on the author's work than in conventional reviews and in aspects neglected in previous reviews, but not in the main feature namely the work of a scientist with comprehensive expertise in a field in which, over long time, he/she continuously performed research and published. A scientist complying with these requirements is a contemporary witness in that field. His report on the scientific achievements in that period, a CWR, comprises confirmation and putative re-interpretation of data from a superior viewpoint. Identification of serotonin's vascular properties (publication year: 1912) as an "adrenaline mimicking substance" (without attempt to isolate it) by O'Connor preceded the discovery of serotonin in the gastrointestinal tract by Erspamer [1937] and in blood by Rapport [1948, 1949], who identified its structure as 5-hydroxytryptamine [1949]. Detection as a neurotransmitter in invertebrates suggested its occurrence in vertebrate CNS as well. This was verified by finding it in dog, rat and rabbit brain [1953]. The Falck-Hillarp technique [1962] visualized serotonin neurones as fluorescent structures. The neurotoxin 5,7-dihydroxytryptamine [1972] indirectly proved the involvement of 5-HT in multiple CNS functions.
Topics: Animals; Central Nervous System; History, 20th Century; Models, Neurological; Mollusca; Neurotoxins; Peripheral Nervous System; Receptors, Serotonin; Review Literature as Topic; Serotonin
PubMed: 24145072
DOI: 10.1016/s1734-1140(13)71059-4