共查询到20条相似文献,搜索用时 31 毫秒
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Anthony J. Hutchinson Randall L. Hudson Margarita L. Dubocovich 《Journal of pineal research》2012,53(4):399-409
Abstract: This study explored the role of the melatonin receptors in methamphetamine (METH)‐induced locomotor sensitization during the light and dark phases in C3H/HeN mice with genetic deletion of the MT1 and/or MT2 melatonin receptors. Six daily treatments with METH (1.2 mg/kg, i.p.) in a novel environment during the light phase led to the development of locomotor sensitization in wild‐type (WT), MT1KO and MT2KO mice. Following four full days of abstinence, METH challenge (1.2 mg/kg, i.p.) triggered the expression of locomotor sensitization in METH‐pretreated but not in vehicle (VEH)‐pretreated mice. In MT1/MT2KO mice, the development of sensitization during the light phase was significantly reduced and the expression of sensitization was completely abrogated upon METH challenge. During the dark phase the development of locomotor sensitization in METH‐pretreated WT, MT1KO and MT2KO mice was statistically different from VEH‐treated controls. However, WT and MT2KO, but not MT1KO mice receiving repeated VEH pretreatments during the dark phase expressed a sensitized response to METH challenge that is of an identical magnitude to that observed upon 6 days of METH pretreatment. We conclude that exposure to a novel environment during the dark phase, but not during the light phase, facilitated the expression of sensitization to a METH challenge in a manner dependent on MT1 melatonin receptor activation by endogenous melatonin. We suggest that MT1 and MT2 melatonin receptors are potential targets for pharmacotherapeutic intervention in METH abusers. 相似文献
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Ludwig Vincent William Cohen Philippe Delagrange Jean A. Boutin Olivier Nosjean 《Journal of pineal research》2010,48(3):222-229
Abstract: 5‐Methoxycarbonylamino‐N‐acetyltryptamine (MCA‐NAT) has been initially described as a ligand at non MT1, non MT2 melatonin binding site (MT3) selective versus MT1 and MT2, two membrane melatonin receptors. MCA‐NAT activity has been reported by others in different models, in vivo, particularly in the intra‐ocular pressure (IOP) models in rabbits and monkeys. Its activity was systematically linked to either MT3 or to a new, yet unknown, melatonin receptor. In this article, the melatonin receptor pharmacology of MCA‐NAT is described. MCA‐NAT has micromolar range affinities at the melatonin receptors MT1 and MT2, while in functional studies, MCA‐NAT proved to be a powerful MT1/MT2 partial agonist in the sub‐micromolar range. These data strongly suggest that MCA‐NAT actions might be mediated by these receptors in vivo. Finally, as described by others, we show that MCA‐NAT is unable to elicit any type of receptor‐like functional responses from Chinese hamster ovary cells over‐expressing quinone reductase 2, the MT3. 相似文献
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Sei‐Jung Lee Young Hyun Jung Sang Yub Oh Seung Pil Yun Ho Jae Han 《Journal of pineal research》2014,57(4):393-407
Melatonin, a circadian rhythm–promoting molecule, has a variety of biological functions, but the functional role of melatonin in the motility of mesenchymal stem cells (MSCs) has yet to be studied. In a mouse skin excisional wound model, we found that transplantation of umbilical cord blood (UCB)‐MSCs pretreated with melatonin enhanced wound closure, granulation, and re‐epithelialization at mouse skin wound sites, where relatively more UCB‐MSCs which were engrafted onto the wound site were detected. Thus, we identified the signaling pathway of melatonin, which affects the motility of UCB‐MSCs. Melatonin (1 μm ) significantly increased the motility of UCB‐MSCs, which had been inhibited by the knockdown of melatonin receptor 2 (MT2). We found that Gαq coupled with MT2 and that the binding of Gαq to MT2 uniquely stimulated an atypical PKC isoform, PKCζ. Melatonin induced the phosphorylation of FAK and paxillin, which were concurrently downregulated by blocking of the PKC activity. Melatonin increased the levels of active Cdc42 and Arp2/3, and it has the ability to stimulate cytoskeletal reorganization‐related proteins such as profilin‐1, cofilin‐1, and F‐actin in UCB‐MSCs. Finally, a lack of MT2 expression in UCB‐MSCs during a mouse skin transplantation experiment resulted in impaired wound healing and less engraftment of stem cells at the wound site. These results demonstrate that melatonin signaling via MT2 triggers FAK/paxillin phosphorylation to stimulate reorganization of the actin cytoskeleton, which is responsible for Cdc42/Arp2/3 activation to promote UCB‐MSCs motility. 相似文献
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Anatomical and cellular localization of melatonin MT1 and MT2 receptors in the adult rat brain
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Baptiste Lacoste Sara Calderoni Alessandro Mauro Franco Fraschini Gabriella Gobbi 《Journal of pineal research》2015,58(4):397-417
The involvement of melatonin in mammalian brain pathophysiology has received growing interest, but information about the anatomical distribution of its two G‐protein‐coupled receptors, MT1 and MT2, remains elusive. In this study, using specific antibodies, we examined the precise distribution of both melatonin receptors immunoreactivity across the adult rat brain using light, confocal, and electron microscopy. Our results demonstrate a selective MT1 and MT2 localization on neuronal cell bodies and dendrites in numerous regions of the rat telencephalon, diencephalon, and mesencephalon. Confocal and ultrastructural examination confirmed the somatodendritic nature of MT1 and MT2 receptors, both being localized on neuronal membranes. Overall, striking differences were observed in the anatomical distribution pattern of MT1 and MT2 proteins, and the labeling often appeared complementary in regions displaying both receptors. Somadendrites labeled for MT1 were observed for instance in the retrosplenial cortex, the dentate gyrus of the hippocampus, the islands of Calleja, the medial habenula, the suprachiasmatic nucleus, the superior colliculus, the substantia nigra pars compacta, the dorsal raphe nucleus, and the pars tuberalis of the pituitary gland. Somadendrites endowed with MT2 receptors were mostly observed in the CA3 field of the hippocampus, the reticular thalamic nucleus, the supraoptic nucleus, the inferior colliculus, the substantia nigra pars reticulata, and the ventrolateral periaqueductal gray. Together, these data provide the first detailed neurocytological mapping of melatonin receptors in the adult rat brain, an essential prerequisite for a better understanding of melatonin distinct receptor function and neurophysiology. 相似文献
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Erika Cecon Anna Ivanova Marine Luka Florence Gbahou Anne Friederich Jean‐Luc Guillaume Patrick Keller Klaus Knoch Raise Ahmad Philippe Delagrange Michele Solimena Ralf Jockers 《Journal of pineal research》2019,66(2)
Melatonin receptors play important roles in the regulation of circadian and seasonal rhythms, sleep, retinal functions, the immune system, depression, and type 2 diabetes development. Melatonin receptors are approved drug targets for insomnia, non‐24‐hour sleep‐wake disorders, and major depressive disorders. In mammals, two melatonin receptors (MTRs) exist, MT1 and MT2, belonging to the G protein‐coupled receptor (GPCR) superfamily. Similar to most other GPCRs, reliable antibodies recognizing melatonin receptors proved to be difficult to obtain. Here, we describe the development of the first monoclonal antibodies (mABs) for mouse MT1 and MT2. Purified antibodies were extensively characterized for specific reactivity with mouse, rat, and human MT1 and MT2 by Western blot, immunoprecipitation, immunofluorescence, and proximity ligation assay. Several mABs were specific for either mouse MT1 or MT2. None of the mABs cross‐reacted with rat MTRs, and some were able to react with human MTRs. The specificity of the selected mABs was validated by immunofluorescence microscopy in three established locations (retina, suprachiasmatic nuclei, pituitary gland) for MTR expression in mice using MTR‐KO mice as control. MT2 expression was not detected in mouse insulinoma MIN6 cells or pancreatic beta‐cells. Collectively, we report the first monoclonal antibodies recognizing recombinant and native mouse melatonin receptors that will be valuable tools for future studies. 相似文献
6.
Abla Benleulmi‐Chaachoua Lina Chen Kate Sokolina Victoria Wong Igor Jurisica Michel Boris Emerit Michèle Darmon Almudena Espin Igor Stagljar Petra Tafelmeyer Gerald W. Zamponi Philippe Delagrange Pascal Maurice Ralf Jockers 《Journal of pineal research》2016,60(1):95-108
In mammals, the hormone melatonin is mainly produced by the pineal gland with nocturnal peak levels. Its peripheral and central actions rely either on its intrinsic antioxidant properties or on binding to melatonin MT1 and MT2 receptors, belonging to the G protein‐coupled receptor (GPCR) super‐family. Melatonin has been reported to be involved in many functions of the central nervous system such as circadian rhythm regulation, neurotransmission, synaptic plasticity, memory, sleep, and also in Alzheimer's disease and depression. However, little is known about the subcellular localization of melatonin receptors and the molecular aspects involved in neuronal functions of melatonin. Identification of protein complexes associated with GPCRs has been shown to be a valid approach to improve our understanding of their function. By combining proteomic and genomic approaches we built an interactome of MT1 and MT2 receptors, which comprises 378 individual proteins. Among the proteins interacting with MT1, but not with MT2, we identified several presynaptic proteins, suggesting a potential role of MT1 in neurotransmission. Presynaptic localization of MT1 receptors in the hypothalamus, striatum, and cortex was confirmed by subcellular fractionation experiments and immunofluorescence microscopy. MT1 physically interacts with the voltage‐gated calcium channel Cav2.2 and inhibits Cav2.2‐promoted Ca2+ entry in an agonist‐independent manner. In conclusion, we show that MT1 is part of the presynaptic protein network and negatively regulates Cav2.2 activity, providing a first hint for potential synaptic functions of MT1. 相似文献
7.
Nocturnal activation of melatonin receptor type 1 signaling modulates diurnal insulin sensitivity via regulation of PI3K activity
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Sharon Owino Aida Sánchez‐Bretaño Cynthia Tchio Erika Cecon Angeliki Karamitri Julie Dam Ralf Jockers Giuseppe Piccione Hye Lim Noh Taekyoon Kim Jason K. Kim Kenkichi Baba Gianluca Tosini 《Journal of pineal research》2018,64(3)
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Melatonin‐mediated inhibition of Purkinje neuron P‐type Ca2+ channels in vitro induces neuronal hyperexcitability through the phosphatidylinositol 3‐kinase‐dependent protein kinase C delta pathway
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Yicheng Pu Shan Gong Chunfeng Liu Xinghong Jiang Jin Tao 《Journal of pineal research》2015,58(3):321-334
Although melatonin receptors are widely expressed in the mammalian central nervous system and peripheral tissues, there are limited data regarding the functions of melatonin in cerebellar Purkinje cells. Here, we identified a novel functional role of melatonin in modulating P‐type Ca2+ channels and action‐potential firing in rat Purkinje neurons. Melatonin at 0.1 μm reversibly decreased peak currents (IBa) by 32.9%. This effect was melatonin receptor 1 (MTR1) dependent and was associated with a hyperpolarizing shift in the voltage dependence of inactivation. Pertussis toxin pretreatment, intracellular application of QEHA peptide, and a selective antibody raised against the Gβ subunit prevented the inhibitory effects of melatonin. Pretreatment with phosphatidylinositol 3‐kinase (PI3K) inhibitors abolished the melatonin‐induced decrease in IBa. Surprisingly, melatonin responses were not regulated by Akt, a common downstream target of PI3K. Melatonin treatment significantly increased protein kinase C (PKC) activity 2.1‐fold. Antagonists of PKC, but not of protein kinase A, abolished the melatonin‐induced decrease in IBa. Melatonin application increased the membrane abundance of PKCδ, and PKCδ inhibition (either pharmacologically or genetically) abolished the melatonin‐induced IBa response. Functionally, melatonin increased spontaneous action‐potential firing by 53.0%; knockdown of MTR1 and blockade of P‐type channels abolished this effect. Thus, our results suggest that melatonin inhibits P‐type channels through MTR1 activation, which is coupled sequentially to the βγ subunits of Gi/o‐protein and to downstream PI3K‐dependent PKCδ signaling. This likely contributes to its physiological functions, including spontaneous firing of cerebellar Purkinje neurons. 相似文献
10.
The tryptophan derivative melatonin is an evolutionary old molecule that is involved in a pleiotropy of physiological functions. In humans, age‐related decline of circulating melatonin levels and/or dysregulation of its circadian synthesis pattern have been associated with several disorders and disease states. Several molecular targets have been proposed for melatonin since its discovery, in 1959. Among them, melatonin MT1 and MT2 receptors are the best characterized melatonin targets, mediating melatonin effects in a variety of tissues. They belong to the superfamily of G protein‐coupled receptors. Two back‐to‐back articles published in the “Nature” Journal earlier this year present the first crystal structures of the human MT1 and MT2 in its inactive states. Here, we will briefly outline the discovery path of melatonin receptors until their structural elucidation and discuss how these new findings will guide future research toward a better understanding of their function and rational drug design. 相似文献
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Melatonin‐mediated inhibition of Cav3.2 T‐type Ca2+ channels induces sensory neuronal hypoexcitability through the novel protein kinase C‐eta isoform
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Yuan Zhang Heyi Ji Jiangong Wang Yufang Sun Zhiyuan Qian Xinghong Jiang Terrance P. Snutch Yangang Sun Jin Tao 《Journal of pineal research》2018,64(4)
Recent studies implicate melatonin in the antinociceptive activity of sensory neurons. However, the underlying mechanisms are still largely unknown. Here, we identify a critical role of melatonin in functionally regulating Cav3.2 T‐type Ca2+ channels (T‐type channel) in trigeminal ganglion (TG) neurons. Melatonin inhibited T‐type channels in small TG neurons via the melatonin receptor 2 (MT2 receptor) and a pertussis toxin‐sensitive G‐protein pathway. Immunoprecipitation analyses revealed that the intracellular subunit of the MT2 receptor coprecipitated with Gαo. Both shRNA‐mediated knockdown of Gαo and intracellular application of QEHA peptide abolished the inhibitory effects of melatonin. Protein kinase C (PKC) antagonists abolished the melatonin‐induced T‐type channel response, whereas inhibition of conventional PKC isoforms elicited no effect. Furthermore, application of melatonin increased membrane abundance of PKC‐eta (PKCη) while antagonism of PKCη or shRNA targeting PKCη prevented the melatonin‐mediated effects. In a heterologous expression system, activation of MT2 receptor strongly inhibited Cav3.2 T‐type channel currents but had no effect on Cav3.1 and Cav3.3 current amplitudes. The selective Cav3.2 response was PKCη dependent and was accompanied by a negative shift in the steady‐state inactivation curve. Furthermore, melatonin decreased the action potential firing rate of small TG neurons and attenuated the mechanical hypersensitivity in a mouse model of complete Freund's adjuvant‐induced inflammatory pain. These actions were inhibited by T‐type channel blockade. Together, our results demonstrated that melatonin inhibits Cav3.2 T‐type channel activity through the MT2 receptor coupled to novel Gβγ‐mediated PKCη signaling, subsequently decreasing the membrane excitability of TG neurons and pain hypersensitivity in mice. 相似文献
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Enhancement of high glucose‐induced PINK1 expression by melatonin stimulates neuronal cell survival: Involvement of MT2/Akt/NF‐κB pathway
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Xaykham Onphachanh Hyun Jik Lee Jae Ryong Lim Young Hyun Jung Jun Sung Kim Chang Woo Chae Sei‐Jung Lee Amr Ahmed Gabr Ho Jae Han 《Journal of pineal research》2017,63(2)
Hyperglycemia is a representative hallmark and risk factor for diabetes mellitus (DM) and is closely linked to DM‐associated neuronal cell death. Previous investigators reported on a genome‐wide association study and showed relationships between DM and melatonin receptor (MT), highlighting the role of MT signaling by assessing melatonin in DM. However, the role of MT signaling in DM pathogenesis is unclear. Therefore, we investigated the role of mitophagy regulators in high glucose‐induced neuronal cell death and the effect of melatonin against high glucose‐induced mitophagy regulators in neuronal cells. In our results, high glucose significantly increased PTEN‐induced putative kinase 1 (PINK1) and LC‐3B expressions; as well it decreased cytochrome c oxidase subunit 4 expression and Mitotracker? fluorescence intensity. Silencing of PINK1 induced mitochondrial reactive oxygen species (ROS) accumulation and mitochondrial membrane potential impairment, increased expressions of cleaved caspases, and increased the number of annexin V‐positive cells. In addition, high glucose‐stimulated melatonin receptor 1B (MTNR1B) mRNA and PINK1 expressions were reversed by ROS scavenger N‐acetyl cysteine pretreatment. Upregulation of PINK1 expression in neuronal cells is suppressed by pretreatment with MT2 receptor‐specific inhibitor 4‐P‐PDOT. We further showed melatonin stimulated Akt phosphorylation, which was followed by nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) phosphorylation and nuclear translocation. Silencing of PINK1 expression abolished melatonin‐regulated mitochondrial ROS production, cleaved caspase‐3 and caspase‐9 expressions, and the number of annexin V‐positive cells. In conclusion, we have demonstrated the melatonin stimulates PINK1 expression via an MT2/Akt/NF‐κB pathway, and such stimulation is important for the prevention of neuronal cell apoptosis under high glucose conditions. 相似文献
15.
Shuai Gao Zhi‐Long Wang Ke‐Qian Di Gang Chang Li Tao Lei An Fu‐Jia Wu Ji‐Qiang Xu Ying‐Wei Liu Zhong‐Hong Wu Xiang‐Yun Li Shaorong Gao Jian‐Hui Tian 《Journal of pineal research》2013,55(1):31-39
This study focused on the effect of melatonin on reprogramming with specific regard to the generation of induced pluripotent stem cells (iPSCs). Here, a secondary inducible system, which is more accurate and suitable for studying the involvement of chemicals in reprogramming efficiency, was used to evaluate the effect of melatonin on mouse iPSC generation. Secondary fibroblasts collected from all‐iPSC mice through tetraploid complementation were cultured in induction medium supplemented with melatonin at different concentrations (0, 10?6, 10?7, 10?8, 10?9, or 10?10 m ) or with vitamin C (50 μg/mL) as a positive control. Compared with untreated group (0.22 ± 0.04% efficiency), 10?8 (0.81 ± 0.04%), and 10?9 m (0.83 ± 0.08%) melatonin supplementation significantly improved reprogramming efficiency (P < 0.05). Moreover, we verified that the iPSCs induced by melatonin treatment (MiPSCs) had the same characteristics as typical embryonic stem cells (ESCs), including expression of the pluripotency markers Oct4, Sox2, and Nanog, the ability to form teratomas and all three germ layers of the embryo, as well as produce chimeric mice with contribution to the germ line. Interestingly, only the melatonin receptor MT2 was detected in secondary fibroblasts, while MiPSCs and ESCs expressed MT1 and MT2 receptors. Furthermore, during the early stage of reprogramming, expression of the apoptosis‐related genes p53 and p21 was lower in the group treated with 10?9 m melatonin compared with the untreated controls. In conclusion, melatonin supplementation enhances the efficiency of murine iPSC generation. These beneficial effects may be associated with inhibition of the p53‐mediated apoptotic pathway. 相似文献
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Nyurky Matheus Carmen Mendoza Ruth Iceta José Emilio Mesonero Ana Isabel Alcalde 《Journal of pineal research》2010,48(4):332-339
Abstract: Gastrointestinal serotonin (5‐HT) and melatonin are two closely related neuromodulators which are synthesised in the enterochromaffin cells of the intestinal epithelium and which have been shown to be involved in the physiopathology of the gastrointestinal tract. The effects of 5‐HT depend on 5‐HT availability which is, in part, modulated by the serotonin transporter (SERT). This transporter provides an efficient 5‐HT uptake after release and is expressed in the membrane of the enterocytes. Although the origin and effects of 5‐HT and melatonin are similar, the interrelationship between them in the gastrointestinal tract is unknown. The main aim of this study was to determine whether melatonin affects SERT activity and expression, and, if so, to elucidate the mechanisms involved. Caco‐2 cell line was used to carry out the study as these cells have been shown to endogenously express SERT. The results showed that melatonin inhibits SERT activity by affecting both Vmax and kt kinetic constants although SERT synthesis or intracellular trafficking did not appear to be affected. The melatonin effect seemed to be independent of melatonin receptors MT1 and MT2 and protein kinase C and cAMP intracellular pathways. Our results suggest that the inhibition of SERT might be due to a catalytic effect of melatonin on the allosteric citalopram‐sensitive site in SERT. This study shows, for the first time, that melatonin modulates SERT activity, thus demonstrating the feedback system between melatonin and the serotoninergic system in the gastrointestinal tract. 相似文献
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Virginia Soria Èrika Martínez‐Amorós Geòrgia Escaramís Joaquín Valero José M. Crespo Alfonso Gutiérrez‐Zotes Mònica Bayés Lourdes Martorell Elisabet Vilella Xavier Estivill José M. Menchón Mònica Gratacòs Mikel Urretavizcaya 《Journal of pineal research》2010,49(1):35-44
Abstract: Circadian rhythms disruptions, including abnormalities of circadian phase position and melatonin secretion, have been described in major depression (MD). Arylalkylamine N‐acetyltransferase (AANAT) is a key enzyme of the melatonin pathway involved in circadian oscillations of melatonin levels. We assessed the contribution of AANAT gene variability to susceptibility to MD considering common and rare genetic variations through a sequential sequencing and single nucleotide polymorphism (SNP)‐based genotyping approach in a sample of 445 unrelated patients with MD (257 unipolar MD, 188 bipolar depression) and 440 community‐based screened control subjects. We identified 17 sequence changes, thirteen of which represented novel sequence variations. We did not observe an over‐representation of patients carrying rare variants compared with the healthy controls. Common variants (MAF > 2%) were included in a case–control association analysis that showed significant association after multiple testing correction of two SNPs located in the promoter region of AANAT with MD: rs3760138 (P = 0.00006) and rs4238989 (P = 0.005). Multimarker analysis found significant associations between two three‐marker protective haplotypes and a susceptibility three‐marker haplotype containing the rare alleles of rs3760138‐rs4238989‐rs8150 and MD. We present evidence of the association of genetic variability in the AANAT gene with susceptibility to MD. Our results support the hypothesis that the melatonin‐signaling pathway and circadian clock mechanisms may contribute to the pathophysiology of MD. 相似文献