RESUMEN

A nuclear retinoic acid receptor (RAR)-related orphan receptor ß (RORß) is strictly expressed in the brain, particularly in the pineal gland where melatonin is primarily synthesized and concentrated. The controversial issues regarding the direct interaction of melatonin toward ROR receptors have prompted us to investigate the potential melatonin binding sites on different ROR isoforms. We adopted computational and biophysical approaches to investigate the potential of melatonin as the ligand for RORs, in particular RORß. Herein, possible melatonin binding sites were predicted by molecular docking on human RORs. The results showed that melatonin might be able to bind within the ligand-binding domain (LBD) of all RORs, despite their difference in sequence homology. The predicted melatonin binding scores were comparable to binding energies with respect to those of melatonin interaction to the well-characterized membrane receptors, MT1 and MT2. Although the computational analyses suggested the binding potential of melatonin to the LBD of RORß, biophysical validation failed to confirm the binding. Melatonin was unable to alter the stability of human RORß as shown by the unaltered melting temperatures upon melatonin administration in differential scanning fluorometry (DSF). A thermodynamic isothermal titration calorimetry (ITC) profile showed that melatonin did not interact with human RORß in solutions, even in the presence of SRC-1 co-activator peptide. Although the direct interaction between the LBD of RORß could not be established, RORα and RORß gene expressions were increased upon 24 h treatment with µM-range melatonin. Our data, thus, support the studies that the nuclear effects of melatonin may not be directly mediated via its interaction with the RORß. These findings warrant further investigation on how melatonin interacts with ROR signaling and urge the melatonin research community for a paradigm shift in the direct interaction of melatonin toward RORs. The quest to identify nuclear receptors for melatonin in neuronal cells remains valid for the community to achieve.

RESUMEN

5-Methoxy-3-(5-methoxyindolin-2-yl)-1H-indole (3), whose structure was unambiguously elucidated by X-ray analysis, was identified as a multi-target compound with potential application in neurodegenerative diseases. It is a low nanomolar inhibitor of QR2 (IC50 = 7.7 nM), with greater potency than melatonin and comparable efficacy to the most potent QR2 inhibitors described to date. Molecular docking studies revealed the potential binding mode of 3 to QR2, which explains its superior potency compared to melatonin. Furthermore, compound 3 inhibits hMAO-A, hMAO-B and hLOX-5 in the low micromolar range and is an excellent ROS scavenger. In phenotypic assays, compound 3 showed neuroprotective activity in a cellular model of oxidative stress damage, it was non-toxic, and was able to activate neurogenesis from neural stem-cell niches of adult mice. These excellent biological properties, together with its both good in silico and in vitro drug-like profile, highlight compound 3 as a promising drug candidate for neurodegenerative diseases.

Asunto(s)

Melatonina , Simulación del Acoplamiento Molecular , Neurogénesis , Fármacos Neuroprotectores , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/síntesis química , Melatonina/farmacología , Melatonina/química , Animales , Ratones , Humanos , Relación Estructura-Actividad , Neurogénesis/efectos de los fármacos , Estructura Molecular , Descubrimiento de Drogas , Quinona Reductasas/antagonistas & inhibidores , Quinona Reductasas/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Relación Dosis-Respuesta a Droga

RESUMEN

This contribution reviews the role of inbred and transgenic mouse strains for deciphering the mammalian melatoninergic and circadian system. It focusses on the pineal organ as melatonin factory and two major targets of the melatoninergic system, the suprachiasmatic nuclei (SCN) and the hypophysial pars tuberalis (PT). Mammalian pinealocytes sharing molecular characteristics with true pineal and retinal photoreceptors synthesize and secrete melatonin into the blood and cerebrospinal fluid night by night. Notably, neuron-like connections exist between the deep pinealocytes and the habenular/pretectal region suggesting direct pineal-brain communication. Control of melatonin biosynthesis in rodents involves transcriptional regulation including phosphorylation of CREB and upregulation of mPer1. In the SCN, melatonin acts upon MT1 and MT2 receptors. Melatonin is not necessary to maintain the rhythm of the SCN molecular clockwork, but it has distinct effects on the synchronization of the circadian rhythm by light, facilitates re-entrainment of the circadian system to phase advances in the level of the SCN molecular clockwork by acting upon MT2 receptors and plays a stabilizing role in the circadian system as evidenced from locomotor activity recordings. While the effects in the SCN are subtle, melatonin is essential for PT functions. Via the MT1 receptor it drives the PT-intrinsic molecular clockwork and the retrograde and anterograde output pathways controlling seasonal rhythmicity. Although inbred and transgenic mice do not show seasonal reproduction, the pathways from the PT are fully intact if the animals are melatonin proficient. Thus, only melatonin-proficient strains are suited to investigate the circadian and melatoninergic systems.

Asunto(s)

Ritmo Circadiano , Melatonina , Animales , Melatonina/metabolismo , Ritmo Circadiano/fisiología , Ratones , Modelos Animales , Núcleo Supraquiasmático/metabolismo , Ratones Transgénicos , Glándula Pineal/metabolismo

RESUMEN

Increasing evidence has shown that many environmental and toxic factors can cause testicular damage, leading to testicular ferroptosis and subsequent male reproductive disorders. Melatonin is a major hormone and plays an vital role in regulating male reproduction. However, there is a lack of research on whether Mel can alleviate testicular cell ferroptosis and its specific mechanism. In this study, the results indicated that Mel could enhance the viability of swine testis cells undergoing ferroptosis, reduce LDH enzyme release, increase mitochondrial membrane potential, and affect the expression of ferroptosis biomarkers. Furthermore, we found that melatonin depended on melatonin receptor 1B to exert these functions. Detection of MMP and ferroptosis biomarker protein expression confirmed that MT2 acted through the downstream Akt signaling pathway. Moreover, inhibition of the Akt signaling pathway can eliminate the protective effect of melatonin on ferroptosis, inhibit AMPK phosphorylation, reduce the expression of mitochondrial gated channel (VDAC2/3), and affect mitochondrial DNA transcription and ATP content. These results suggest that melatonin exerts a beneficial effect on mitochondrial function to mitigate ferroptosis through the MT2/Akt signaling pathway in ST cells.

Asunto(s)

Ferroptosis , Melatonina , Mitocondrias , Proteínas Proto-Oncogénicas c-akt , Receptor de Melatonina MT2 , Transducción de Señal , Testículo , Animales , Melatonina/farmacología , Masculino , Ferroptosis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Porcinos , Testículo/metabolismo , Testículo/efectos de los fármacos , Receptor de Melatonina MT2/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos

RESUMEN

Psychological stress affects the neuroendocrine regulation, which modulates mental status and behaviors. Melatonin, a hormone synthesized primarily by the pineal gland, regulates many brain functions, including circadian rhythms, pain, sleep, and mood. Selective pharmacological melatonin agonist ramelteon has been clinically used to treat mood and sleep disorders. Posttraumatic stress disorder (PTSD) is a psychiatric condition associated with severe trauma; it is generally triggered by traumatic events, which lead to severe anxiety and uncontrollable trauma recall. We recently reported that repeated social defeat stress (RSDS) may induce robust anxiety-like behaviors and social avoidance in mice. In the present study, we investigated whether melatonin receptor activation by melatonin and ramelteon regulates RSDS-induced behavioral changes. Melatonin treatment improved social avoidance and anxiety-like behaviors in RSDS mice. Moreover, treatment of the non-selective MT1/MT2 receptor agonist, ramelteon, markedly ameliorated RSDS-induced social avoidance and anxiety-like behaviors. Moreover, activating melatonin receptors also balanced the expression of monoamine oxidases, glucocorticoid receptors, and endogenous antioxidants in the hippocampus. Taken together, our findings indicate that the activation of both melatonin and ramelteon regulates RSDS-induced anxiety-like behaviors and PTSD symptoms. The current study also showed that the regulatory effects of neuroendocrine mechanisms and cognitive behaviors on melatonin receptor activation in repeated social defeat stress.

Asunto(s)

Ansiedad , Indenos , Melatonina , Derrota Social , Estrés Psicológico , Animales , Indenos/farmacología , Ratones , Masculino , Estrés Psicológico/metabolismo , Estrés Psicológico/tratamiento farmacológico , Melatonina/farmacología , Ansiedad/tratamiento farmacológico , Ansiedad/psicología , Conducta Animal/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/agonistas , Receptor de Melatonina MT1/agonistas , Receptor de Melatonina MT1/metabolismo , Receptor de Melatonina MT2/agonistas , Receptor de Melatonina MT2/metabolismo , Ratones Endogámicos C57BL , Monoaminooxidasa/metabolismo , Receptores de Melatonina/agonistas , Receptores de Melatonina/metabolismo , Trastornos por Estrés Postraumático/tratamiento farmacológico , Trastornos por Estrés Postraumático/psicología , Trastornos por Estrés Postraumático/metabolismo

RESUMEN

Adipose-derived mesenchymal stem cells (ASCs) are adult multipotent stem cells, able to differentiate toward neural elements other than cells of mesodermal lineage. The aim of this research was to test ASC neural differentiation using melatonin combined with conditioned media (CM) from glial cells. Isolated from the lipoaspirate of healthy donors, ASCs were expanded in a basal growth medium before undergoing neural differentiation procedures. For this purpose, CM obtained from olfactory ensheathing cells and from Schwann cells were used. In some samples, 1 µM of melatonin was added. After 1 and 7 days of culture, cells were studied using immunocytochemistry and flow cytometry to evaluate neural marker expression (Nestin, MAP2, Synapsin I, GFAP) under different conditions. The results confirmed that a successful neural differentiation was achieved by glial CM, whereas the addition of melatonin alone did not induce appreciable changes. When melatonin was combined with CM, ASC neural differentiation was enhanced, as demonstrated by a further improvement of neuronal marker expression, whereas glial differentiation was attenuated. A dynamic modulation was also observed, testing the expression of melatonin receptors. In conclusion, our data suggest that melatonin's neurogenic differentiation ability can be usefully exploited to obtain neuronal-like differentiated ASCs for potential therapeutic strategies.

Asunto(s)

Diferenciación Celular , Melatonina , Células Madre Mesenquimatosas , Melatonina/farmacología , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Humanos , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Tejido Adiposo/citología , Neuronas/citología , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Medios de Cultivo Condicionados/farmacología , Células de Schwann/citología , Células de Schwann/metabolismo , Células de Schwann/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Adulto , Nestina/metabolismo , Nestina/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Neuroglía/efectos de los fármacos , Neuroglía/citología , Neuroglía/metabolismo , Sinapsinas/metabolismo

RESUMEN

Melatonin (5-methoxy-N-acetyltryptamine) binds with high affinity and specificity to membrane receptors. Several receptor subtypes exist in different species, of which the mammalian MT1 and MT2 receptors are the best-characterized. They are members of the G protein-coupled receptor superfamily, preferentially coupling to Gi/o proteins but also to other G proteins in a cell-context-depending manner. In this review, experts on melatonin receptors will summarize the current state of the field. We briefly report on the discovery and classification of melatonin receptors, then focus on the molecular structure of human MT1 and MT2 receptors and highlight the importance of molecular simulations to identify new ligands and to understand the structural dynamics of these receptors. We then describe the state-of-the-art of the intracellular signaling pathways activated by melatonin receptors and their complexes. Brief statements on the molecular toolbox available for melatonin receptor studies and future perspectives will round-up this review.

Asunto(s)

Melatonina , Receptor de Melatonina MT1 , Animales , Humanos , Receptores de Melatonina , Receptor de Melatonina MT1/metabolismo , Receptor de Melatonina MT2/metabolismo , Melatonina/metabolismo , Transducción de Señal , Receptores Acoplados a Proteínas G , Mamíferos/metabolismo

RESUMEN

The labeled ligand commonly employed in competition binding studies for melatonin receptor ligands, 2-[125I]iodomelatonin, showed slow dissociation with different half-lives at the two receptor subtypes. This may affect the operational measures of affinity constants, which at short incubation times could not be obtained in equilibrium conditions, and structure-activity relationships, as the Ki values of tested ligands could depend on either interaction at the binding site or the dissociation path. To address these issues, the kinetic and saturation binding parameters of 2-[125I]iodomelatonin as well as the competition constants for a series of representative ligands were measured at a short (2 h) and a long (20 h) incubation time. Concurrently, we simulated by molecular modeling the dissociation path of 2-iodomelatonin from MT1 and MT2 receptors and investigated the role of interactions at the binding site on the stereoselectivity observed for the enantiomers of the subtype-selective ligand UCM1014. We found that equilibrium conditions for 2-[125I]iodomelatonin binding can be reached only with long incubation times, particularly for the MT2 receptor subtype, for which a time of 20 h approximates this condition. On the other hand, measured Ki values for a set of ligands including agonists, antagonists, nonselective, and subtype-selective compounds were not significantly affected by the length of incubation, suggesting that structure-activity relationships based on data collected at shorter time reflect different interactions at the binding site. Molecular modeling simulations evidenced that the slower dissociation of 2-iodomelatonin from the MT2 receptor can be related to the restricted mobility of a gatekeeper tyrosine along a lipophilic path from the binding site to the membrane bilayer. The enantiomers of the potent, MT2-selective agonist UCM1014 were separately synthesized and tested. Molecular dynamics simulations of the receptor-ligand complexes provided an explanation for their stereoselectivity as due to the preference shown by the eutomer at the binding site for the most abundant axial conformation adopted by the ligand in solution. These results suggest that, despite the slow-binding kinetics occurring for the labeled ligand, affinity measures at shorter incubation times give robust results consistent with known structure-activity relationships and with interactions taken at the receptor binding site.

Asunto(s)

Melatonina , Quinolinas , Ligandos , Receptores de Melatonina , Melatonina/metabolismo , Amidas , Receptor de Melatonina MT2/metabolismo , Receptor de Melatonina MT1/metabolismo

RESUMEN

Day length is a critical environmental factor for regulating animal growth and development. This study aimed to investigate the effects of different day lengths on the developmental changes of growth parameters, testicular sizes, testosterone secretion in Meishan male pigs, and steroidogenesis proteins and melatonin receptors. Fourteen Meishan male pigs (10 weeks (wks) of age) with the same parity, paired in litter and body weight (BW), were evenly allocated into a short-day-length group (SDL, 10 light/14 dark) and long-day-length group (LDL, 14 light/10 dark). After 12 wks of the experiment, the LDL-treated boars had more lying time and less exploring time. The LDL treatment led to significant increases in body height, chest circumference, testicular length, testicular weight, crude protein digestibility, and fecal testosterone at the 10th and 12th wks of the experiment, and cortisol at the 10th wk, compared to the SDL treatment, with no differences in the final BW, testicular width, and epididymis weight. Furthermore, the LDL treatment significantly increased the protein levels of melatonin receptor 1b (MT2), aromatase (CYP19), and steroidogenic factor 1 (SF1) in the testis, with no differences in the protein levels of melatonin receptor 1a (MT1), steroidogenic acute regulatory (StAR), 3ß-hydroxysteroid dehydrogenase (3ß-HSD), and cholesterol side-chain cleavage enzyme (P450scc). The present study suggests that day length has an effect on the growth and gonadal development in male pigs maybe via MT2 and influences steroid synthesis and secretion in the testis. Therefore, proper day length should be considered in male pig breeding.

RESUMEN

Aim: The pathogenesis of chronic diabetes complications has oxidative stress as one of the major elements, and single-nucleotide polymorphisms (SNPs) in genes belonging to antioxidant pathways modulate susceptibility to these complications. Considering that melatonin is a powerful antioxidant compound, our aim was to explore, in a longitudinal cohort study of type 1 diabetes (T1D) individuals, the association of microvascular complications and SNPs in the gene encoding melatonin receptor 1A (MTNR1A). Methods: Eight SNPs in MTNR1A were genotyped in 489 T1D individuals. Besides cross-sectional analyses of SNPs with each one of the microvascular complications (distal polyneuropathy, cardiovascular autonomic neuropathy, retinopathy, and diabetic kidney disease), a longitudinal analysis evaluated the associations of SNPs with renal function decline in 411 individuals followed up for a median of 8 years. In a subgroup of participants, the association of complications with urinary 6-sulfatoxymelatonin (aMT6s) concentration was investigated. Results: The group of individuals with a renal function decline ≥ 5 mL min-1 1.73 m-2 year-1 presented a higher frequency of the A allele of rs4862705 in comparison with nondecliners, even after adjustment for confounding variables (OR = 1.84, 95% CI = 1.20-2.82; p = 0.0046). No other significant associations were found. Conclusions: This is the first study showing an association between a variant in a gene belonging to the melatonin system and renal function decline in the diabetic setting.

Asunto(s)

Diabetes Mellitus Tipo 1 , Melatonina , Humanos , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/genética , Antioxidantes , Receptores de Melatonina , Estudios Transversales , Estudios Longitudinales , Riñón

RESUMEN

Background: Melatonin is an indoleamine hormone secreted by the pineal gland at night and has an essential role in regulating human circadian rhythms (the internal 24-h clock) and sleep-wake patterns. However, it has recently gained considerable attention for its demonstrated ability in disease management. This review discusses the major biological activities of melatonin, its metabolites as nutritional supplements, and its bioavailability in food sources. Methods: The information acquisition process involved conducting a comprehensive search across academic databases including PubMed, Scopus, Wiley, Embase, and Springer using relevant keywords. Only the most recent, peer-reviewed articles published in the English language were considered for inclusion. Results: The molecular mechanisms by which melatonin induces its therapeutic effects have been the subject of various studies. Conclusion: While melatonin was initially understood to only regulate circadian rhythms, recent studies indicate that it has a far-reaching effect on various organs and physiological systems, such as immunity, cardiovascular function, antioxidant defense, and lipid hemostasis. As a potent antioxidant, anti-cancer, anti-inflammatory, and immunoregulatory agent, multiple therapeutic applications have been proposed for melatonin.

RESUMEN

Evidence suggests that the neuroprotective effects of melatonin involve both receptor-dependent and -independent actions. However, little is known about the effects of melatonin receptor activation on the kainate (KA) neurotoxicity. This study examined the effects of repeated post-KA treatment with ramelteon, a selective agonist of melatonin receptors, on neuronal loss, cognitive impairment, and depression-like behaviors following KA-induced seizures. The expression of melatonin receptors decreased in neurons, whereas it was induced in astrocytes 3 and 7 days after seizures elicited by KA (0.12 µg/µL) in the hippocampus of mice. Ramelteon (3 or 10 mg/kg, i.p.) and melatonin (10 mg/kg, i.p.) mitigated KA-induced oxidative stress and impairment of glutathione homeostasis and promoted the nuclear translocation and DNA binding activity of Nrf2 in the hippocampus after KA treatment. Ramelteon and melatonin also attenuated microglial activation but did not significantly affect astroglial activation induced by KA, despite the astroglial induction of melatonin receptors after KA treatment. However, ramelteon attenuated KA-induced proinflammatory phenotypic changes in astrocytes. Considering the reciprocal regulation of astroglial and microglial activation, these results suggest ramelteon inhibits microglial activation by regulating astrocyte phenotypic changes. These effects were accompanied by the attenuation of the nuclear translocation and DNA binding activity of nuclear factor κB (NFκB) induced by KA. Consequently, ramelteon attenuated the KA-induced hippocampal neuronal loss, memory impairment, and depression-like behaviors; the effects were comparable to those of melatonin. These results suggest that ramelteon-mediated activation of melatonin receptors provides neuroprotection against KA-induced neurotoxicity in the mouse hippocampus by activating Nrf2 signaling to attenuate oxidative stress and restore glutathione homeostasis and by inhibiting NFκB signaling to attenuate neuroinflammatory changes.

Asunto(s)

Indenos , Melatonina , Ratones , Animales , Melatonina/farmacología , Melatonina/metabolismo , Receptores de Melatonina/metabolismo , Ácido Kaínico/toxicidad , Ácido Kaínico/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Hipocampo , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Convulsiones/metabolismo , Glutatión/metabolismo , ADN

RESUMEN

Alterations in circadian sleep patterns constitute a salient manifestation in major depressive disorder. GW117, an emergent antidepressant, functions as an agonist for melatonin 1 and melatonin 2 (MT1/MT2) receptors, in tandem with antagonism of the serotonin (5-HT) 2C receptor. The present investigation is dedicated to elucidating the role and underlying mechanisms by which GW117 ameliorates circadian sleep disruptions. Utilizing an adapted chronic unpredictable mild stress protocol, we induced a depressive-like phenotype and perturbed circadian rhythms in rodent models. Our methodological approach integrated quantitative polymerase chain reaction (qPCR) in real-time, enzyme-linked immunosorbent assay (ELISA), and immunoblotting techniques to probe alterations in the expression of core circadian genes and homeostatic sleep markers. The impact of GW117 was assessed across various dosages (10, 20, and 40 mg/kg) on these molecular signatures. In a parallel examination, we evaluated the influence of GW117 (administered at 15, 40, and 60 mg/kg) on the sleep patterns of healthy mice. The results showed that GW117 significantly improved sleep-wake circadian rhythms, altered sleep architecture, and shortened sleep latency. Furthermore, GW117 increased the expression of several clock genes in the hypothalamus of chronic unpredictable mild stress model rats and normal mice. It also regulated circadian biomarkers, including melatonin and cortisol. Based on our findings, we propose that the beneficial effects of GW117 on sleep rhythms may be due to the melatonin system-mediated activation of the Wnt/ß-catenin signaling pathway.

Asunto(s)

Trastorno Depresivo Mayor , Melatonina , Ratas , Animales , Ratones , Trastorno Depresivo Mayor/tratamiento farmacológico , Melatonina/uso terapéutico , Sueño , Ritmo Circadiano , Receptor de Melatonina MT1/metabolismo , Receptor de Melatonina MT2/agonistas , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Serotonina/farmacología , Compuestos Orgánicos

RESUMEN

In recent years, more and more attention of researchers has been paid to the study of dilated cardiomyopathy (DCMP). The prevalence of this disease in older age groups is higher than previously thought, and the course of the disease is associated with a worse prognosis and treatment difficulties. Researchers are considering various signaling molecules whose expression changes are associated with myocardial damage and the development of DCMP; evaluation of changes in the expression of melatonin and its receptors in DCMP requires further study. The aim of the study was to study the age-related features of the expression of melatonin and its receptors (MT1, MT2) in the myocardium and their changes depending on the presence of dilated cardiomyopathy. Immunocytochemical and immunohistochemical methods were used to evaluate the expression of melatonin and its MT1, MT2 receptors in myocardial autopsy material and cardiomyocyte cultures of people of different ages with and without cardiovascular pathology. The study revealed age-associated changes in the form of a decrease in the expression of melatonin and its MT1 and MT2 receptors in the myocardium. In individuals with DCMP of all age groups, a more significant decrease in expression was noted: melatonin by 1,6-1,7 times in old age and 3,2 times in old age; MT1 by 1,8 and 2 times, respectively; MT2 by 1,4 and 4 times, respectively. The relationship between the decrease in the expression of melatonin and its receptors in myocardial tissues with age and the presence of DCMP was revealed. The data obtained allow us to clarify age-dependent changes in melatonin and its receptors, as well as to assume their important role in the development of DCMP, which requires further study.

Asunto(s)

Cardiomiopatía Dilatada , Melatonina , Humanos , Anciano , Melatonina/metabolismo , Cardiomiopatía Dilatada/diagnóstico , Desoxicitidina Monofosfato , Receptor de Melatonina MT1/metabolismo , Miocardio/metabolismo , Receptor de Melatonina MT2/metabolismo

RESUMEN

The pineal hormone melatonin is a multi-functional molecule with a recognized role in pigment aggregation in chromatophores, mediating its actions through binding to subtypes of its specific receptors. Since its discovery, melatonin has been known to be responsible for pigment aggregation towards the cell centre in fishes, including their embryos, as an adaptation to reduced light and thus results in pale body colouration. Diversity exists in the sensitivity of melanophores towards melatonin at interspecies, intraspecific levels, seasons, and amongst chromatophores at different regions of the animal body. In most of the fishes, melatonin leads to their skin paling at night. It is indicated that the melatonin receptors have characteristically maintained to show the same aggregating effects in fishes and other vertebrates in the evolutionary hierarchy. However, besides this aggregatory effect, melatonin is also responsible for pigment dispersion in certain fishes. Here is the demand in our review to explore further the nature of the dispersive behaviour of melatonin through the so-called ß-melatonin receptors. It is clear that the pigment translocations in lower vertebrates under the effect of melatonin are mediated through the melatonin receptors coupled with other hormonal receptors as well. Therefore, being richly supplied with a variety of receptors, chromatophores and melanocytes can be used as in vitro test models for pharmacological applications of known and novel drugs. In this review, we present diverse effects of melatonin on chromatophores of fishes in particular with appropriate implications on most of the recent findings.

Asunto(s)

Cromatóforos , Melatonina , Animales , Melatonina/farmacología , Melatonina/metabolismo , Receptores de Melatonina/metabolismo , Peces/metabolismo , Melanóforos , Vertebrados/metabolismo

RESUMEN

As a receptor for plant melatonin, CAND2/PMTR plays an important role in melatonin signaling. Most of the CANDs are membrane proteins and play indispensable roles in signal transduction. In this study, the CANDs from four cotton species were characterized, and the phylogenetic relationships, expression patterns, stress responses of cotton CANDs were analyzed by bioinformatics. Through the analysis of phylogenetic and protein structure, it was found that the CANDs in clade Ⅱ might function as cotton melatonin receptors, and most of the GhCANDs in clade Ⅱ were induced by melatonin. A putative cotton melatonin receptor, GhCAND2-D5, was functionally probed by gene silencing. The plants with silenced expression of this gene exhibited decreased salt tolerance. Protein interaction prediction identified that GhCAND2-D5 interacted with several membrane proteins and played an important role in melatonin signaling. This study provided a theoretical reference for further investigation of melatonin signaling in cotton.

RESUMEN

The presence of signaling-competent G protein-coupled receptors in intracellular compartments is increasingly recognized. Recently, the presence of Gi/o protein-coupled melatonin MT1 receptors in mitochondria has been revealed, in addition to the plasma membrane. Melatonin is highly cell permeant, activating plasma membrane and mitochondrial receptors equally. Here, we present MCS-1145, a melatonin derivative bearing a triphenylphosphonium cation for specific mitochondrial targeting and a photocleavable o-nitrobenzyl group releasing melatonin upon illumination. MCS-1145 displayed low affinity for MT1 and MT2 but spontaneously accumulated in mitochondria, where it was resistant to washout. Uncaged MCS-1145 and exogenous melatonin recruited ß-arrestin 2 to MT1 in mitochondria and inhibited oxygen consumption in mitochondria isolated from HEK293 cells only when expressing MT1 and from mouse cerebellum of WT mice but not from MT1-knockout mice. Overall, we developed the first mitochondria-targeted photoactivatable melatonin ligand and demonstrate that melatonin inhibits mitochondrial respiration through mitochondrial MT1 receptors.

Asunto(s)

Melatonina , Receptor de Melatonina MT1 , Animales , Humanos , Ratones , Receptor de Melatonina MT1/metabolismo , Melatonina/farmacología , Melatonina/metabolismo , Células HEK293 , Receptores Acoplados a Proteínas G/metabolismo , Mitocondrias/metabolismo , Respiración

RESUMEN

The population of T lymphocytes producing IL-17 (Th17) plays a dual role during pregnancy and its activity is tightly controlled during this period. One of the factors involved in this process may be the pineal hormone melatonin, which can effectively regulate this T cell population. Here we have shown that exogenous melatonin in pharmacological concentrations is able to enhance the differentiation of Th17 cells of pregnant women in vitro. The stimulatory effects of melatonin were limited to in the first trimester of pregnancy and were apparently mediated by both membrane and nuclear melatonin receptors. Since exogenous melatonin is currently considered as a promising drug in solving various problems associated with reproduction, it is necessary to take into account its immunoregulatory effects.

RESUMEN

Melatonin (MT) is a crucial neuroendocrine regulator of various physiological activities in vertebrates, especially in circadian or seasonal rhythm control. In the present study, the large yellow croaker (Larimichthys crocea), a marine bony fish with circadian body color change behavior, is chosen for functional investigation on teleost MT signaling systems that remain uncharacterized. All five melatonin receptors (LcMtnr1a1, LcMtnr1a2, LcMtnr1b1, LcMtnr1b2, and LcMtnr1c) were significantly activated by MT, triggering extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation through different G protein coupling signaling pathways, with exclusive Gαi-dependency for LcMtnr1a2 and LcMtnr1c, and Gαq-dependency for two LcMtnr1b paralogs, whereas LcMtnr1a1 activated Gαi and Gαs dual-dependent signaling pathways. A comprehensive model of the MT signaling system in the hypothalamic-pituitary neuroendocrine axis was further constructed based on ligand-receptor interaction analysis using single-cell RNA-seq data, as well as spatial expression patterns of Mtnrs and related neuropeptides in central neuroendocrine tissues. A novel regulatory pathway of MT/melanin-concentrating hormone (MCH) and MT/(tachykinin precursor 1 (TAC1)+corticotropin-releasing hormone (CRH))/melanocyte-stimulating hormone (MSH) was discovered that functions in chromatophore mobilization and physiological color change and was further validated by pharmacological experiments. Together, our findings define multiple intracellular signaling pathways mediated by L. crocea melatonin receptors and provide the first in-depth evidence that uncover the upstream modulating roles of the MT signaling system in the hypothalamic-pituitary neuroendocrine axis of a marine teleost species, particularly in chromatophore mobilization and physiological color change.

Asunto(s)

Melatonina , Neuropéptidos , Animales , Melatonina/farmacología , Melatonina/metabolismo , Receptores de Melatonina , Hormona Liberadora de Corticotropina , Transducción de Señal

RESUMEN

BACKGROUND: The purpose of this study is to investigate the association of rotating night shift work, CLOCK, MTNR1A, MTNR1B genes polymorphisms and their interactions with type 2 diabetes among steelworkers. METHODS: A case-control study was conducted in the Tangsteel company in Tangshan, China. The sample sizes of the case group and control group were 251 and 451, respectively. The logistic regression, log-linear model and generalized multifactor dimensionality (GMDR) method were used to investigate the interaction between circadian clock gene, melatonin receptor genes and rotating night shift work on type 2 diabetes among steelworkers. Relative excess risk due to interaction (RERI) and attributable proportions (AP) were used to evaluate additive interactions. RESULTS: Rotating night shift work, current shift status, duration of night shifts, and average frequency of night shifts were associated with an increased risk of type 2 diabetes after adjustment for confounders. Rs1387153 variants in MTNR1B was found to be associated with an increased risk of type 2 diabetes, which was not found between MTNR1A gene rs2119882 locus, CLOCK gene rs1801260 locus and the risk of type 2 diabetes. The association between rotating night shift work and risk of type 2 diabetes appeared to be modified by MTNR1B gene rs1387153 locus (RERI = 0.98, (95% CI, 0.40-1.55); AP = 0.60, (95% CI, 0.07-1.12)). The interaction between MTNR1A gene rs2119882 locus and CLOCK gene rs1801260 locus was associated with the risk of type 2 diabetes (RERI = 1.07, (95% CI, 0.23-1.91); AP = 0.77, (95% CI, 0.36-1.17)). The complex interaction of the MTNR1A-MTNR1B-CLOCK-rotating night shift work model based on the GMDR methods may increase the risk of type 2 diabetes (P = 0.011). CONCLUSIONS: Rotating night shift work and rs1387153 variants in MTNR1B were associated with an increased risk of type 2 diabetes among steelworkers. The complex interaction of MTNR1A-MTNR1B-CLOCK-rotating night shift work may increase the risk of type 2 diabetes.

Asunto(s)

Relojes Circadianos , Diabetes Mellitus Tipo 2 , Horario de Trabajo por Turnos , Humanos , Estudios de Casos y Controles , Relojes Circadianos/genética , Ritmo Circadiano/genética , Diabetes Mellitus Tipo 2/genética , Polimorfismo Genético , Receptor de Melatonina MT1/genética , Receptor de Melatonina MT2/genética , Horario de Trabajo por Turnos/efectos adversos