Membrane Melatonin Receptors Activated Cell Signaling in Physiology and Disease.
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ABSTRACT:
SUBMITTER: Nikolaev G
PROVIDER: S-EPMC8745360 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Many of melatonin's actions are mediated through interaction with the G-protein coupled membrane bound melatonin receptors type 1 and type 2 (MT1 and MT2, respectively) or, indirectly with nuclear orphan receptors from the ROR?/RZR family. Melatonin also binds to the quinone reductase II enzyme, previously defined the MT3 receptor. Melatonin receptors are widely distributed in the body; herein we summarize their expression and actions in non-neural tissues. Several controversies still exist regarding, for example, whether melatonin binds the ROR?/RZR family. Studies of the peripheral distribution of melatonin receptors are important since they are attractive targets for immunomodulation, regulation of endocrine, reproductive and cardiovascular functions, modulation of skin pigmentation, hair growth, cancerogenesis, and aging. Melatonin receptor agonists and antagonists have an exciting future since they could define multiple mechanisms by which melatonin modulates the complexity of such a wide variety of physiological and pathological processes.
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Project description:PurposePrevious studies have demonstrated that melatonin has an important role in the modulation of photoreceptor viability during aging and may be involved in the pathogenesis of age-related macular degeneration.This hormone exerts its influence by binding to G-protein coupled receptors named melatonin receptor 1 (MT1) and 2 (MT2). Melatonin receptors 1 and 2 activate a wide variety of signaling pathways.MethodsMelatonin-proficient mice (C3H/f+/+) and melatonin-proficient mice lacking MT1 or MT2 receptors (MT1-/- and MT2-/-) were used in this study. Mice were killed at the ages of 3 and 18 months, and photoreceptor viability was determined by counting nuclei number in the outer nuclear layer (ONL). Cones were identified by immunohistochemistry using peanut agglutinin (PNA) and green/red and blue opsin antibodies. Protein kinase B (AKT) and forkhead box O (FOXO1) were assessed by Western blotting and immunohistochemistry.ResultsThe number of nuclei in the ONL was significantly reduced in C3Hf+/+, MT1-/-, and MT2-/- mice at 18 months of age with respect to 3-month-old animals. In 18-month-old MT1-/- and MT2-/- mice, but not in C3H/f+/+, the number of cones was significantly reduced with respect to young MT1-/- and MT2-/- mice or age-matched C3H/f+/+. In C3H/f+/+, activation of the AKT-FOXO1 pathway in the photoreceptors showed a significant difference between night and day.ConclusionsOur data indicate that disruption of MT1/MT2 heteromer signaling induces a reduction in the number of photoreceptors during aging and also suggest that the AKT-FOXO1 survival pathway may be involved in the mechanism by which melatonin protects photoreceptors.
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Project description:Melatonin is a key regulator of follicle granular cell maturation and ovulation. The mammalian target of rapamycin (mTOR) pathway plays an important role in cell growth regulation. Therefore, our aim was to investigate whether the mTOR signaling pathway is involved in the regulation of melatonin-mediated proliferation and apoptotic mechanisms in granulosa cells. Chicken follicle granular cells were cultured with melatonin (0, 2, 20, or 200 ?mol/L) for 48 h. The results showed that melatonin treatment enhanced proliferation and suppressed apoptosis in granular cells at 20 ?mol/L and 200 ?mol/L (P < 0.05) by upregulation of cyclin D1 (P < 0.01) and Bcl-2 (P < 0.01) and downregulation of P21, caspase-3, Beclin1, and LC3-II (P < 0.01). The effects resulted in the activation of the mTOR signaling pathway by increasing the expression of avTOR, PKC, 4E-BP1, S6K (P < 0.05), p-mTOR, and p-S6K. We added an mTOR activator and inhibitor to the cells and identified the optimal dose (10 ?mol/L MHY1485 and 100 nmol/L rapamycin) for subsequent experiments. The combination of 20 ?mol/L melatonin and 10 ?mol/L MHY1485 significantly enhanced granulosa cell proliferation (P < 0.05), while 100 nmol/L rapamycin significantly inhibited proliferation and enhanced apoptosis (P < 0.05), but this action was reversed in the 20-?mol/L melatonin and 100-nmol/L rapamycin cotreatment groups (P < 0.05). This was confirmed by mRNA and protein expression that was associated with proliferation, apoptosis, and autophagy (P < 0.05). The combination of 20 ?mol/L melatonin and 10 ?mol/L MHY1485 also activated the mTOR pathway upstream genes PI3K, AKT1, and AKT2 and downstream genes PKC, 4E-BP1, and S6K (P < 0.05), as well as protein expression of p-mTOR and p-S6K. Rapamycin significantly inhibited the mTOR pathway-related genes mRNA levels (P < 0.05). In addition, activation of the mTOR pathway increased melatonin receptor mRNA levels (P < 0.05). In conclusion, these findings demonstrate that melatonin regulates chicken granulosa cell proliferation and apoptosis by activating the mTOR signaling pathway via its receptor.
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Project description:Melatonin receptors (MT1 and MT2 in humans) are family A G protein-coupled receptors that respond to the neurohormone melatonin to regulate circadian rhythm and sleep. Numerous efforts have been made to develop drugs targeting melatonin receptors for the treatment of insomnia, circadian rhythm disorder, and cancer. However, designing subtype-selective melatonergic drugs remains challenging. Here, we report the cryo-EM structures of the MT1-Gi signaling complex with 2-iodomelatonin and ramelteon and the MT2-Gi signaling complex with ramelteon. These structures, together with the reported functional data, reveal that although MT1 and MT2 possess highly similar orthosteric ligand-binding pockets, they also display distinctive features that could be targeted to design subtype-selective drugs. The unique structural motifs in MT1 and MT2 mediate structural rearrangements with a particularly wide opening on the cytoplasmic side. Gi is engaged in the receptor core shared by MT1 and MT2 and presents a conformation deviating from those in other Gi complexes. Together, our results provide new clues for designing melatonergic drugs and further insights into understanding the G protein coupling mechanism.
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Project description:To gain a better understanding of the diurnal variation in gene expression, we analyzed the changes in gene expression in the eye of zebrafish. Dual color oligonucleotide microarrays were used to compare total RNA harvested from eyes of adult zebrafish at midday and midnight. Statistical analyses identified 44 genes which showed significant, 2-fold or more change; 26 genes showed decreased expression at midnight (D/L ≤ 0.5) and 18 genes showed increased expression at midnight (D/L ≥ 2). Seven genes were further analyzed using qPCR. The results of qPCR identified AANAT, Mel1a1, Mel1a3, Mel1b1, Mel1b2 and Melc as genes that showed significant change in expression at dawn, dusk, midday and midnight. These results suggest that expression of melatonin receptors is subject to diurnal regulation. Wild-type ZDR zebrafish (Danio rerio) were obtained from Animal Wonders, San Marcos, TX, and Aquatica Tropicals, Plant City, FL. Fish were conditioned on a 12 hour light/dark cycle for a minimum of 14 days before use. The design of this analysis compared the experimental to the control: midnight samples were used as experimental and midday as control. Samples were collected in triplicate per time point with each replicate representing total RNA pooled from 9 fish. Dual-color microarray was used to compare the midnight and midday samples. A statistically significant (p-value ≤ 0.05) and 2-fold or more change in an experimental sample as compared to a control indicated an up- or down-regulation in gene expression. Supplementary files: In Complete processed data file, "x" marked spots show intensities of less than 1000. In Intensity trimmed data file, all genes with signal intensities of less than 1000 in all triplicate time points were removed from the analysis.
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