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Human Reproduction (Oxford, England) Jul 2019Are melatonin receptors (melatonin receptor 1A (MR1A) and melatonin receptor 1B (MR1B)) expressed in human endometrium and endometriotic tissue, and does melatonin...
STUDY QUESTION
Are melatonin receptors (melatonin receptor 1A (MR1A) and melatonin receptor 1B (MR1B)) expressed in human endometrium and endometriotic tissue, and does melatonin affect endometrial cell proliferation?
SUMMARY ANSWER
Melatonin receptors are expressed in human eutopic endometrium, endometriomas and peritoneal lesions, although to different extents, and melatonin treatment attenuated estradiol-induced endometrial epithelial cell proliferation in culture.
WHAT IS KNOWN ALREADY
Melatonin decreased endometriotic lesion volume in a rat model of endometriosis. Melatonin treatment reduced pain scores in and analgesic use by women with endometriosis.
STUDY DESIGN, SIZE, DURATION
Basic science study using human endometrial tissue and an endometrial epithelial cell line.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Measurement of melatonin receptor expression (mRNA and protein) in women with surgically confirmed endometriosis (endometrioma (n = 20) or peritoneal lesion (n = 11) alone) and women without surgical evidence of endometriosis (control, n = 15). Collection of endometrial and endometriotic tissue samples, gynecologic history and demographic information. Quantification of estradiol (1.0 nM) and melatonin (0.1 nM-1.0 μM) ± estradiol-induced endometrial epithelial cell proliferation in cultures of endometrial epithelial cells (CRL-1671) following 24 and 48 hours of culture.
MAIN RESULTS AND THE ROLE OF CHANCE
MR1A and MR1B were localized by immunohistochemistry in glandular epithelial cells of endometrial biopsies from women with and without endometriosis. Both receptors were expressed in eutopic and ectopic endometrial tissue. mRNA expression of MR1A and MR1B was significantly greater in peritoneal lesions than in either endometriomas or eutopic endometrium. However, protein expression of MR1A was decreased in peritoneal lesions compared to control eutopic endometrium, whereas MR1B expression did not differ between the groups. Melatonin (0.1 nM-1.0 μM) treatment inhibited estradiol (1.0 nM)-induced endometrial epithelial cell proliferation at 48 hours but not 24 hours of culture.
LIMITATIONS, REASONS FOR CAUTION
Beneficial effects of melatonin seen in culture have yet to be comprehensively evaluated in women with endometriosis.
WIDER IMPLICATIONS OF THE FINDINGS
Our data suggest that melatonin may be useful as an adjunct to current endometriosis treatments.
STUDY FUNDING/COMPETING INTEREST(S)
This study was supported by the Canadian Institutes of Health Research (grant MOP142230 to W.G.F.). A.A.M. is supported by a resident research grant through the Physicians Services Incorporated Foundation. The authors have no conflicts of interest.
Topics: Adult; Case-Control Studies; Cell Line, Tumor; Cell Proliferation; Endometriosis; Endometrium; Female; Humans; Melatonin; Receptors, Melatonin
PubMed: 31211323
DOI: 10.1093/humrep/dez082 -
CNS Neuroscience & Therapeutics Mar 2024Postoperative sleep disorder (PSD) and delirium, which may be associated with surgery and inhalational anesthetics, induce adverse effects in old adults. Emerging...
BACKGROUND
Postoperative sleep disorder (PSD) and delirium, which may be associated with surgery and inhalational anesthetics, induce adverse effects in old adults. Emerging evidence indicates that circadian rhythm contributes to various neuropathological diseases, including Alzheimer's disease. Thus, we analyzed the potential role of circadian rhythm in PSD and delirium-like behavior in aged mice and determined whether exogenous melatonin could facilitate entrainment of the circadian rhythm after laparotomy under sevoflurane anesthesia.
METHODS
We selected old C57BL/6J mice which receiving laparotomy/sevoflurane anesthesia as model animals. We employed buried food, open field, and Y maze test to assess delirium-like behavior, and electroencephalography/electromyography (EEG/EMG) were used to investigate sleep changes. We analyzed the transcription rhythm of clock genes in superchiasmatic nucleus (SCN) to explore the effects of surgery and melatonin pretreatment on the circadian rhythm. Then, we measured melatonin receptor levels in SCN and ERK/CREB pathway-related proteins in hippocampus and prefrontal cortex to assess their role in PSDs and delirium-like behavior.
RESULTS
Laparotomy under sevoflurane anesthesia had a greater influence than sevoflurane alone, leading to sleep disorder, a shift in sleep-wake rhythm, and delirium-like behavior. Bmal1, Clock, and Cry1 mRNA expression showed a peak shift, MT melatonin receptor expression level was increased in the SCN, and p-ERK/ERK and p-CREB/CREB were decreased in hippocampus and prefrontal cortex of aged mice 1 day after laparotomy. Melatonin showed significant efficacy in ameliorating PSD and delirium-like behavior and restoring the circadian rhythm, reversing melatonin receptor and ERK/CREB pathway expression abnormalities. In addition, most of the beneficial effect of melatonin was antagonized by luzindole, a melatonin receptor antagonist.
CONCLUSIONS
Melatonin receptors in SCN, circadian rhythm, and ERK/CREB signaling pathway participate in the pathophysiological processes of PSD and delirium-like behavior. Melatonin intervention could be a potential preventative approach for PSD and delirium.
Topics: Animals; Mice; Melatonin; Receptors, Melatonin; Sevoflurane; Mice, Inbred C57BL; Circadian Rhythm; Delirium; Sleep Wake Disorders
PubMed: 37736695
DOI: 10.1111/cns.14436 -
International Journal of Molecular... May 2013Melatonin receptors are members of the G protein-coupled receptor (GPCR) family. Three genes for melatonin receptors have been cloned. The MT1 (or Mel1a or MTNR1A) and... (Review)
Review
Melatonin receptors are members of the G protein-coupled receptor (GPCR) family. Three genes for melatonin receptors have been cloned. The MT1 (or Mel1a or MTNR1A) and MT2 (or Mel1b or MTNR1B) receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype, Mel1c (or MTNR1C), has been identified in fish, amphibians and birds. Another melatonin related orphan receptor, GPR50, which does not bind melatonin, is found exclusively in mammals. The hormone melatonin is secreted primarily by the pineal gland, with highest levels occurring during the dark period of a circadian cycle. This hormone acts systemically in numerous organs. In the brain, it is involved in the regulation of various neural and endocrine processes, and it readjusts the circadian pacemaker, the suprachiasmatic nucleus. This article reviews recent studies of gene organization, expression, evolution and mutations of melatonin receptor genes of vertebrates. Gene polymorphisms reveal that numerous mutations are associated with diseases and disorders. The phylogenetic analysis of receptor genes indicates that GPR50 is an outgroup to all other melatonin receptor sequences. GPR50 may have separated from a melatonin receptor ancestor before the split between MTNR1C and the MTNR1A/B ancestor.
Topics: Amino Acid Sequence; Animals; Evolution, Molecular; Gene Expression Regulation; Humans; Molecular Sequence Data; Nerve Tissue Proteins; Polymorphism, Genetic; Receptors, Melatonin; Vertebrates
PubMed: 23712359
DOI: 10.3390/ijms140611208 -
American Journal of Physiology. Lung... Dec 2021Nocturnal asthma is characterized by heightened bronchial reactivity at night, and plasma melatonin concentrations are higher in patients with nocturnal asthma symptoms....
Nocturnal asthma is characterized by heightened bronchial reactivity at night, and plasma melatonin concentrations are higher in patients with nocturnal asthma symptoms. Numerous physiological effects of melatonin are mediated via its specific G protein-coupled receptors (GPCRs) named the MT receptor, which couples to both G and G proteins, and the MT receptor, which couples to G. We investigated whether melatonin receptors are expressed on airway smooth muscle; whether they regulate intracellular cyclic AMP (cAMP) and calcium concentrations ([Ca]), which modulate airway smooth muscle tone; and whether they promote airway smooth muscle cell proliferation. We detected the mRNA and protein expression of the melatonin MT but not the MT receptor in native human and guinea pig airway smooth muscle and cultured human airway smooth muscle (HASM) cells by RT-PCR, immunoblotting, and immunohistochemistry. Activation of melatonin MT receptors with either pharmacological concentrations of melatonin (10-100 µM) or the nonselective MT/MT agonist ramelteon (10 µM) significantly inhibited forskolin-stimulated cAMP accumulation in HASM cells, which was reversed by the Gα protein inhibitor pertussis toxin or knockdown of the MT receptor by its specific siRNA. Although melatonin by itself did not induce an initial [Ca] increase and airway contraction, melatonin significantly potentiated acetylcholine-stimulated [Ca] increases, stress fiber formation through the MT receptor in HASM cells, and attenuated the relaxant effect of isoproterenol in guinea pig trachea. These findings suggest that the melatonin MT receptor is expressed in ASM, and modulates airway smooth muscle tone via reduced cAMP production and increased [Ca].
Topics: Acetylcholine; Adult; Animals; Antioxidants; Colforsin; Cyclic AMP; Guinea Pigs; Humans; Male; Melatonin; Middle Aged; Muscle Contraction; Muscle Relaxation; Myocytes, Smooth Muscle; Receptor, Melatonin, MT2; Respiratory System; Vasodilator Agents
PubMed: 34612067
DOI: 10.1152/ajplung.00273.2021 -
British Journal of Pharmacology Sep 2016Melatonin receptors are seven transmembrane-spanning proteins belonging to the GPCR superfamily. In mammals, two melatonin receptor subtypes exist - MT1 and MT2 -... (Review)
Review
Melatonin receptors are seven transmembrane-spanning proteins belonging to the GPCR superfamily. In mammals, two melatonin receptor subtypes exist - MT1 and MT2 - encoded by the MTNR1A and MTNR1B genes respectively. The current review provides an update on melatonin receptors by the corresponding subcommittee of the International Union of Basic and Clinical Pharmacology. We will highlight recent developments of melatonin receptor ligands, including radioligands, and give an update on the latest phenotyping results of melatonin receptor knockout mice. The current status and perspectives of the structure of melatonin receptor will be summarized. The physiological importance of melatonin receptor dimers and biologically important and type 2 diabetes-associated genetic variants of melatonin receptors will be discussed. The role of melatonin receptors in physiology and disease will be further exemplified by their functions in the immune system and the CNS. Finally, antioxidant and free radical scavenger properties of melatonin and its relation to melatonin receptors will be critically addressed.
Topics: Animals; Humans; Ligands; Receptors, Melatonin
PubMed: 27314810
DOI: 10.1111/bph.13536 -
The Plant Journal : For Cell and... Jan 2021Melatonin is a multifunctional biomolecule found in both animals and plants. In this review, the biosynthesis, levels, signaling, and possible roles of melatonin and its... (Review)
Review
Melatonin is a multifunctional biomolecule found in both animals and plants. In this review, the biosynthesis, levels, signaling, and possible roles of melatonin and its metabolites in plants is summarized. Tryptamine 5-hydroxylase (T5H), which catalyzes the conversion of tryptamine into serotonin, has been proposed as a target to create a melatonin knockout mutant presenting a lesion-mimic phenotype in rice. With a reduced anabolic capacity for melatonin biosynthesis and an increased catabolic capacity for melatonin metabolism, all plants generally maintain low melatonin levels. Some plants, including Arabidopsis and Nicotiana tabacum (tobacco), do not possess tryptophan decarboxylase (TDC), the first committed step enzyme required for melatonin biosynthesis. Major melatonin metabolites include cyclic 3-hydroxymelatonin (3-OHM) and 2-hydroxymelatonin (2-OHM). Other melatonin metabolites such as N -acetyl-N -formyl-5-methoxykynuramine (AFMK), N-acetyl-5-methoxykynuramine (AMK) and 5-methoxytryptamine (5-MT) are also produced when melatonin is applied to Oryza sativa (rice). The signaling pathways of melatonin and its metabolites act via the mitogen-activated protein kinase (MAPK) cascade, possibly with Cand2 acting as a melatonin receptor, although the integrity of Cand2 remains controversial. Melatonin mediates many important functions in growth stimulation and stress tolerance through its potent antioxidant activity and function in activating the MAPK cascade. The concentration distribution of melatonin metabolites appears to be species specific because corresponding enzymes such as M2H, M3H, catalases, indoleamine 2,3-dioxygenase (IDO) and N-acetylserotonin deacetylase (ASDAC) are differentially expressed among plant species and even among different tissues within species. Differential levels of melatonin and its metabolites can lead to differential physiological effects among plants when melatonin is either applied exogenously or overproduced through ectopic overexpression.
Topics: Genes, Plant; Melatonin; Metabolic Networks and Pathways; Plant Growth Regulators; Plant Physiological Phenomena; Plants; Receptors, Melatonin; Signal Transduction
PubMed: 32645752
DOI: 10.1111/tpj.14915 -
Frontiers in Bioscience (Elite Edition) Jan 2021Melatonin, a hormone which is primarily released by the pineal gland, has a wide range of actions in the female reproductive tract. While the melatonin receptor subtype,... (Review)
Review
Melatonin, a hormone which is primarily released by the pineal gland, has a wide range of actions in the female reproductive tract. While the melatonin receptor subtype, MT3, has been identified in amphibian animals and birds, in humans and other mammals, melatonin acts through, MT1 and MT2 receptor subtypes which are expressed in human ovaries. The rhythmic release of melatonin starts at puberty and continues throughout fertile female life, affecting and regulating diverse ovarian functions. Here, we discuss the importance of melatonin in regulating folliculogenesis, oocyte quality, ovulation and luteal function, sex steroid receptor gene expression, ovarian steroidogenesis including the production and steroidogenic enzyme activities in the egg and thecal cells. Melatonin improves the egg quality and increases the chance of success of in vitro fertilization (IVF). In view of such extensive actions, melatonin is central to the fertility in females. The objective of this review is to recapitulate the current understanding of the role of melatonin and its receptors.
Topics: Animals; Female; Humans; Melatonin; Ovary; Receptor, Melatonin, MT2; Receptors, Melatonin
PubMed: 33048779
DOI: 10.2741/875 -
Cellular and Molecular Gastroenterology... 2022Primary sclerosing cholangitis (PSC) is characterized by biliary senescence and hepatic fibrosis. Melatonin exerts its effects by interacting with Melatonin receptor 1...
BACKGROUND & AIMS
Primary sclerosing cholangitis (PSC) is characterized by biliary senescence and hepatic fibrosis. Melatonin exerts its effects by interacting with Melatonin receptor 1 and 2 (MT1/MT2) melatonin receptors. Short-term (1 wk) melatonin treatment reduces a ductular reaction and liver fibrosis in bile duct-ligated rats by down-regulation of MT1 and clock genes, and in multidrug resistance gene 2 knockout (Mdr2) mice by decreased miR200b-dependent angiogenesis. We aimed to evaluate the long-term effects of melatonin on liver phenotype that may be mediated by changes in MT1/clock genes/miR200b/maspin/glutathione-S transferase (GST) signaling.
METHODS
Male wild-type and Mdr2 mice had access to drinking water with/without melatonin for 3 months. Liver damage, biliary proliferation/senescence, liver fibrosis, peribiliary inflammation, and angiogenesis were measured by staining in liver sections, and by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay in liver samples. We confirmed a link between MT1/clock genes/miR200b/maspin/GST/angiogenesis signaling by Ingenuity Pathway Analysis software and measured liver phenotypes and the aforementioned signaling pathway in liver samples from the mouse groups, healthy controls, and PSC patients and immortalized human PSC cholangiocytes.
RESULTS
Chronic administration of melatonin to Mdr2 mice ameliorates liver phenotypes, which were associated with decreased MT1 and clock gene expression.
CONCLUSIONS
Melatonin improves liver histology and restores the circadian rhythm by interaction with MT1 through decreased angiogenesis and increased maspin/GST activity.
Topics: Animals; Cholangitis, Sclerosing; Cholestasis; Disease Models, Animal; Drinking Water; Glutathione; Humans; Liver Cirrhosis; Male; Melatonin; Mice; Phenotype; Rats; Receptors, Melatonin; Transferases
PubMed: 35863741
DOI: 10.1016/j.jcmgh.2022.07.007 -
Sleep Medicine Clinics Dec 2015Circadian (body clock) timing has a profound influence on mental health, physical health, and health behaviors. This review focuses on how light, melatonin, and other... (Review)
Review
Circadian (body clock) timing has a profound influence on mental health, physical health, and health behaviors. This review focuses on how light, melatonin, and other melatonin receptor agonist drugs can be used to shift circadian timing in patients with misaligned circadian rhythms. A brief overview of the human circadian system is provided, followed by a discussion of patient characteristics and safety considerations that can influence the treatment of choice. The important features of light treatment, light avoidance, exogenous melatonin, and other melatonin receptor agonists are reviewed, along with some of the practical aspects of light and melatonin treatment.
Topics: Central Nervous System Agents; Circadian Rhythm; Humans; Light; Melatonin; Phototherapy; Receptors, Melatonin; Sleep Disorders, Circadian Rhythm
PubMed: 26568121
DOI: 10.1016/j.jsmc.2015.08.001 -
International Journal of Molecular... Sep 2013Melatonin is primarily synthesized and secreted by the pineal gland during darkness in a normal diurnal cycle. In addition to its intrinsic antioxidant property, the... (Review)
Review
Melatonin is primarily synthesized and secreted by the pineal gland during darkness in a normal diurnal cycle. In addition to its intrinsic antioxidant property, the neurohormone has renowned regulatory roles in the control of circadian rhythm and exerts its physiological actions primarily by interacting with the G protein-coupled MT1 and MT2 transmembrane receptors. The two melatonin receptor subtypes display identical ligand binding characteristics and mediate a myriad of signaling pathways, including adenylyl cyclase inhibition, phospholipase C stimulation and the regulation of other effector molecules. Both MT1 and MT2 receptors are widely expressed in the central nervous system as well as many peripheral tissues, but each receptor subtype can be linked to specific functional responses at the target tissue. Given the broad therapeutic implications of melatonin receptors in chronobiology, immunomodulation, endocrine regulation, reproductive functions and cancer development, drug discovery and development programs have been directed at identifying chemical molecules that bind to the two melatonin receptor subtypes. However, all of the melatoninergics in the market act on both subtypes of melatonin receptors without significant selectivity. To facilitate the design and development of novel therapeutic agents, it is necessary to understand the intrinsic differences between MT1 and MT2 that determine ligand binding, functional efficacy, and signaling specificity. This review summarizes our current knowledge in differentiating MT1 and MT2 receptors and their signaling capacities. The use of homology modeling in the mapping of the ligand-binding pocket will be described. Identification of conserved and distinct residues will be tremendously useful in the design of highly selective ligands.
Topics: Animals; Humans; Melatonin; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Receptors, Melatonin; Signal Transduction
PubMed: 24018885
DOI: 10.3390/ijms140918385