NCBI Summary:
This gene encodes one of two high affinity forms of a receptor for melatonin, the primary hormone secreted by the pineal gland. This receptor is a G-protein coupled, 7-transmembrane receptor that is responsible for melatonin effects on mammalian circadian rhythm and reproductive alterations affected by day length. The receptor is an integral membrane protein that is readily detectable and localized to two specific regions of the brain. The hypothalamic suprachiasmatic nucleus appears to be involved in circadian rhythm while the hypophysial pars tuberalis may be responsible for the reproductive effects of melatonin. [provided by RefSeq, Jul 2008]
General function
Receptor
Comment
Cellular localization
Plasma membrane
Comment
family123
Ovarian function
Follicle atresia, Steroid metabolism, Early embryo development
Comment
Knockdown of melatonin receptor 1 and induction of follicle-stimulating hormone on the regulation of mouse granulosa cell function. Talpur HS et al. (2017) Melatonin receptor 1 (MT1) performs a critical role in the regulation of the animal reproductive system, particularly in follicular growth, and has a considerable effect on reproductive performance. However, the role that MT1 plays in regulating hormones associated with reproduction remains unclear. This study was designed to examine the physiological role of constitutive MT1 silencing and follicle stimulating hormone (FSH) treatment in reproduction, making use of mouse granulosa cells (mGCs) as a model. To understand the constitutive role of MT1 in ovarian physiology, the RNAi-Ready pSIREN-RETROQ-ZsGreen Vector mediated recombinant pshRNA was used to silence MT1 gene expression. Furthermore, we observed that the expression of MT1 was successfully inhibited both at the protein and mRNA levels (P<0.001). We demonstrated that RNAi-B-mediated MT1 down-regulation significantly promoted apoptosis (P<0.001), inhibited proliferation, and regulated the cell cycle at the S-phase; conversely, FSH treatment partially aided the apoptotic effect and improved proliferation but showed a significant effect at the S-phase of the cell cycle. Transitory knockdown of MT1 proved essential in the function of mGCs, as it significantly decreased cyclic adenosine monophospahte (cAMP) level and increased cell apoptosis. Following knockdown of MT1, the expression of Bax was significantly up-regulated (P<0.001), but Bcl-2 was slightly down-regulated, both at the transcriptional and at translational levels. Moreover, the silencing of MT1 and its constitutive effect on FSH significantly promoted an increase in estradiol (P<0.001) and slightly decreased the concentration of progesterone. Together, our data indicates that MT1 suppression leads to interference in the normal physiological function of the ovary by enhancing follicular apoptosis, inhibiting proliferation, and influencing hormonal signaling, whereas constitutive FSH treatment counteracted the negative down-regulatory effects of MT1 on mGCs.//////////////////
Melatonin Prevents Post-Ovulatory Oocyte Aging in the Mouse and Extends the Window for Optimal Fertilization In Vitro. Lord T et al. The quality of metaphase II oocytes deteriorates rapidly following ovulation as the result of an aging process associated with impaired fertilizing potential, disrupted developmental competence and an increased likelihood of embryonic resorption. As oxidative stress has been shown to accelerate the onset of apoptosis in oocytes and influence their capacity for fertilization, this study aimed to characterize the significance of such stress in the post-ovulatory aging of mouse oocytes in vitro. In the course of these studies, we investigated the ability of the potent antioxidant, melatonin, to arrest the aging process when used to supplement oocyte culture medium. This study demonstrated that oxidative stress may occur in oocytes after as little as 8 h in culture and coincides with the appearance of early apoptotic markers such as phosphatidylserine externalization, and is followed 16 h later by caspase activation (P < 0.05) and morphological evidence of oocyte senescence (P < 0.001). Importantly, supplementation of oocyte culture medium with 1 mM melatonin was able to significantly relieve the time-dependent appearance of oxidative stress in oocytes (P < 0.05) and, as a result, significantly delay the onset of apoptosis (P < 0.05). Furthermore, melatonin supplementation extended the optimal window for fertilization of oocytes aged for 8 h and 16 h in vitro (P < 0.05), and significantly improved the quality of the resulting embryos (P < 0.01). We conclude that melatonin may be a useful tool in a clinical setting to prevent the time-dependent deterioration of oocyte quality following prolonged culture in vitro.
Melatonin suppresses apoptosis and stimulates progesterone production by bovine granulosa cells via its receptors (MT1 and MT2). Wang SJ et al. Melatonin and its receptors have been detected in the ovary of many species, and mediate ovarian functions. The present study was designed to investigate the expression and subcellar location of melatonin receptors in bovine granulosa cells (GCs), using reverse transcription (RT) polymerase chain reaction, Western blot, and immunofluorescence analyses. Furthermore, expression level of melatonin receptors mRNA (real-time polymerase chain reaction) after treatment with various concentrations of melatonin, as well as its effects on cell apoptosis, proliferation, and steroidogenesis (by flow cytometry and RIA), were determined. In bovine GCs, melatonin receptors MT1 and MT2 were differentially located at the cell membrane, the cytoplasm, and nuclear membranes. The expression of MT1 and MT2 mRNA was regulated differently by melatonin in time- and dose-dependent manners. Exogenous melatonin suppressed cell apoptosis (P < 0.05) but not proliferation (P > 0.05). After 72 h, the apoptotic rate was significantly inhibited in all treatment groups. Meanwhile, melatonin supplementation stimulated progesterone production, but inhibited estradiol biosynthesis, in a time-dependent manner. Progesterone production was highest (P < 0.05) at 72 h. Estradiol concentrations were almost unaffected (P > 0.05) at 24 h, but were decreased (P < 0.05) at 48 h. In conclusion, exogenous melatonin acts via receptors and has important roles in regulation of development and function of bovine GCs.
Expression regulated by
LH
Comment
Melatonin and its receptor MT1 are involved in the downstream reaction to luteinizing hormone and participate in the regulation of luteinization in different species. He C et al. (2016) The functions of melatonin in preovulatory fluid remain elusive. In the current study, we observed that the extremely high level of expression of MT1 in mice granulosa cells was rapidly induced by hCG (equivalent LH) within 2 hours and this was referred as MT1 surge. In cumulus cells, serotonin N-acetyltransferase (SNAT) was also up-regulated by hCG and led to elevated melatonin levels in ovarian follicle fluid. Melatonin application before MT1 surge significantly promoted embryo implantation and this was probably attributed to a rise in progesterone levels in the serum. The mechanistic studies indicated that melatonin/MT1 (MLT/MT1) signaling remarkably improved the expression of corpus luteum marker genes, i.e., Akr1c18, Cyp11a1. High-throughput sequencing results suggested that extracellular matrix (ECM) receptor interaction, focal adhesion and activation of PI3K/Akt pathway which are involved in granulosa cell luteinization might mediate the actions of MLT/MT1 signal. In addition, this effect on luteinization was compared in different species. It was verified that high melatonin levels exist in serum at oestrum of cows and helps to improve the first oestrus fecundation rate. These results suggested that both melatonin and MT1 are involved in the downstream reaction of hCG (LH) and they play important roles in luteinization. These findings provide the novel information on the physiology of melatonin in animal reproduction. This article is protected by copyright. All rights reserved.//////////////////
Ovarian localization
Cumulus
Comment
Daily differential expression of melatonin-related genes and clock genes in rat cumulus-oocyte complex: Changes after pinealectomy. Coelho LA et al. (2015) This study investigated the maturational stage (immature and mature ovaries) differences of mRNA expression of melatonin forming enzymes (Aanat and Asmt), melatonin membrane receptors (Mt1 and Mt2) and putative nuclear (Rorα) receptors and clock genes (Clock, Bmal1, Per1, Per2, Cry1, Cry2) in cumulus-oocyte complexes (COC) from weaning Wistar rats. We also examined the effects of pinealectomy and of melatonin pharmacological replacement on the daily expression of these genes in COC. qRT-PCR analysis revealed that in oocytes, the mRNA expression of Asmt, Mt2, Clock, Bmal1, Per2 and Cry1 were higher (P<0.05) in immature ovaries than in the mature ones. In cumulus cells, the same pattern of mRNA expression for Asmt, Aanat, Rorα, Clock, Per1, Cry1 and Cry2 genes was observed. In oocytes, pinealectomy altered the daily mRNA expression profiles of Asmt, Mt1, Mt2, Clock, Per1, Cry1 and Cry2 genes. In cumulus cells, removal of the pineal altered the mRNA expression profiles of Mt1, Mt2, Rorα, Aanat, Asmt, Clock, Bmal1, Per2, Cry1, and Cry2 genes. Melatonin treatment partially or completely re-established the daily mRNA expression profiles of most genes studied. The mRNA expression of melatonin-related genes and clock genes in rat COC vary with the maturational stage of the meiotic cellular cycle in addition to the hour of the day. This suggests that melatonin might act differentially in accordance to the maturational stage of cumulus/oocyte complex. In addition, it seems that circulating pineal melatonin is very important in the design of the daily profile of mRNA expression of COC clock genes and genes related to melatonin synthesis and action. This article is protected by copyright. All rights reserved.//////////////////
Follicle stages
Comment
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
3 mutations
Species: human
Mutation name: None
type: naturally occurring fertility: subfertile Comment: Melatonin Receptor 1A Gene Polymorphism Associated with Polycystic Ovary Syndrome. Li C et al. Background/Aims: Melatonin receptor 1A (MTNR1A) gene is a regulator of circadian rhythms and reproductive processes. The MTNR1A gene is also a potential candidate gene of polycystic ovary syndrome (PCOS). The aim of the present study was to determine whether or not the MTNR1A gene polymorphism is associated with a predisposition to PCOS. Methods: The single nucleotide polymorphism (SNP) rs2119882 in the MTNR1A gene was detected in 482 patients with PCOS and 522 healthy Chinese Han women. Subsequently, the association of MTNR1A gene variants with plasma glucose, insulin levels during oral glucose tolerance tests (OGTTs) and hormone levels was investigated. Results: The frequencies of genotypes and allelotypes of SNP rs2119882 differed significantly between PCOS cases and healthy controls (p < 0.001 and p = 0.002, respectively). SNP rs2119882 was associated with higher fasting plasma glucose concentrations (p = 0.021) and OGTT-induced insulin release at 0, 30, 60, and 120 min (all p < 0.05) in PCOS cases, as well as an increased homeostasis model assessment for insulin resistance (p = 0.005). Conclusion: SNP rs2119882 is associated with PCOS.
Species: human
Mutation name: type: naturally occurring fertility: subfertile Comment: Family association study between melatonin receptor gene polymorphisms and polycystic ovary syndrome in Han Chinese. Song X et al. (2015) The melatonin receptor (MTNR) gene, reported to be associated with insulin sensitivity, diabetes and metabolic syndrome, could be a plausible candidate gene for polycystic ovary syndrome (PCOS). This study was designed to investigate whether an association exists between two single nucleotide polymorphism (SNP) variants (rs2119882 and rs10830963) of the MTNR gene and PCOS in Han Chinese. In total, 263 family trios (789 participants) were enrolled in this family-based transmission disequilibrium test (TDT). Genotypes were obtained by sequencing. In total, 135 trios of rs2119882 and 127 trios of rs10830963 were tested. An association was detected between rs2119882 (p=0.0209) and PCOS, suggesting that the MTNR gene may indicate increased susceptibility to PCOS in Chinese. No significant association was found for rs10830963 (transmitted:non-transmitted=76:51, p=0.1573). The association between the MTNR gene variants and clinical characteristics of women with PCOS was investigated. CC genotype carriers had higher levels of clinical and metabolic features than the TC and TT genotypes. A significant difference in transmission of allele C of rs2119882 was found between obese and non-obese women with PCOS (Chi-squared=5.5983, p=0.018). This study may provide a basis for further studies of the MTNR gene in the aetiology of PCOS.//////////////////
Species: ovine
Mutation name: type: naturally occurring fertility: fertile Comment: Polymorphisms of the melatonin receptor 1A gene that affect the reproductive seasonality and litter size in Small Tail Han sheep. He X et al. (2019) Previous researches have shown that MTNR1A plays an essential role in sheep reproduction. However, most researches focused more on the reproductive seasonality of sheep, few scientists had studied the association of polymorphisms of the MTNR1A gene with ovine litter size and reproductive seasonality. Therefore, we chose MTNR1A gene to detect its novel sequence polymorphisms, population genetics and analyze their association with seasonal reproduction and litter size in ewes. The mRNA expression level in hypothalamus, pituitary and ovary was also detected. In this study, five polymorphisms (g.15118664G>T, g.15118683C>T, g.15118756C>T, g.15118774C>T and g.15118951G>A) were identified in exon 2. Most importantly, the g.15118683C>T and g.15118951G>A were significant difference between year-round estrous sheep and seasonal estrous sheep (P<0.01), and g.15118756C>T had a great effect on litter size of Small Tail Han sheep (P<0.05). In addition, the mRNA expression level of MTNR1A in the hypothalamus of polytocous Small Tail Han sheep was significantly higher than that in monotocous Small Tail Han sheep (P<0.01) and the expression of MTNR1A in the hypothalamus of year-round estrous sheep was significantly higher than that in seasonal estrous sheep (P<0.01). Polymorphisms in exon 2 may regulate the reproductive seasonality and litter size of ewes by influencing gene expression to. Our studies provided useful guidance in marker-assisted selection of the litter size in Small Tail Han sheep. This article is protected by copyright. All rights reserved.//////////////////