The Endogenous Melatonin (MT) Signal Facilitates Reentrainment of the Circadian System to Light-Induced Phase Advances by Acting Upon MT2 Receptors

Pfeffer, Martina; Rauch, Anke; Korf, Horst‐Werner; Gall, Charlotte von

doi:10.3109/07420528.2012.667859

Cited by 67 publications

(67 citation statements)

References 52 publications

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“…The SCN has been found to be the main regulator of circadian rhythms, which then sends signals to peripheral cells throughout the body, causing that rhythm to be passed on to the proper cells and tissues (53). However, the SCN can be stimulated by zeitgebers other than light, especially by serotonin and melatonin, although these are thought to be internal feedback regulators as opposed to primary circadian rhythm initiators (112,113,128). Melatonin has also been found to be one of the signaling molecules used by the body to synchronize certain peripheral cells.…”

Section: Circadian Rhythms and Zeitgebers: The Tempo Of Lifementioning

confidence: 99%

Circadian Rhythm Connections to Oxidative Stress: Implications for Human Health

Wilking

Ndiaye²,

Mukhtar³

et al. 2013

Antioxidants & Redox Signaling

246

192

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Significance: Oxygen and circadian rhythmicity are essential in a myriad of physiological processes to maintain homeostasis, from blood pressure and sleep/wake cycles, down to cellular signaling pathways that play critical roles in health and disease. If the human body or cells experience significant stress, their ability to regulate internal systems, including redox levels and circadian rhythms, may become impaired. At cellular as well as organismal levels, impairment in redox regulation and circadian rhythms may lead to a number of adverse effects, including the manifestation of a variety of diseases such as heart diseases, neurodegenerative conditions, and cancer. Recent Advances: Researchers have come to an understanding as to the basics of the circadian rhythm mechanism, as well as the importance of the numerous species of oxidative stress components. The effects of oxidative stress and dysregulated circadian rhythms have been a subject of intense investigations since they were first discovered, and recent investigations into the molecular mechanisms linking the two have started to elucidate the bases of their connection. Critical Issues: While much is known about the mechanics and importance of oxidative stress systems and circadian rhythms, the front where they interact has had very little research focused on it. This review discusses the idea that these two systems are together intricately involved in the healthy body, as well as in disease. Future Directions: We believe that for a more efficacious management of diseases that have both circadian rhythm and oxidative stress components in their pathogenesis, targeting both systems in tandem would be far more successful.

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Section: Circadian Rhythms and Zeitgebers: The Tempo Of Lifementioning

confidence: 99%

Circadian Rhythm Connections to Oxidative Stress: Implications for Human Health

Wilking

Ndiaye²,

Mukhtar³

et al. 2013

Antioxidants & Redox Signaling

246

192

View full text Add to dashboard Cite

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“…39 In vitro experiments using ligands toward MLT receptors and SCN slices from wild-type and MLT receptor knockout mice showed that activation of MT 1 receptors inhibited the neuronal firing rate of the SCN, whereas activation of MT 2 receptors phase-shifted circadian rhythms of neuronal firing rates. 26,34,37,40,41 But, in Siberian hamsters in which the MT 1 receptor was functional, but the MT 2 receptor was not, MLT elicited a clear phase shift of the circadian rhythm of SCN electrical activity. 42 In vivo experiments in MLT receptor knockout mice further complicated the scenario.…”

Section: What Are Their Roles?mentioning

confidence: 99%

Unveiling the role of melatonin MT2 receptors in sleep, anxiety and other neuropsychiatric diseases: a novel target in psychopharmacology

Comai

Gobbi

2014

J Psychiatry Neurosci

155

126

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IntroductionMelatonin (MLT) is a neurohormone synthesized from serotonin (5-HT) and secreted foremost by the mammalian pineal gland following a distinct circadian rhythm with the acrophase during the dark phase and the nadir during the light phase in both diurnal and nocturnal species.1 A typical human adult's average daytime and nighttime levels of blood MLT are approximately 10 pg/mL and 60 pg/mL, respectively.2 Its production is controlled through the suprachiasmatic nucleus (SCN) by the photoperiod, peaking at night and dropping during the day. Melatonin is involved in numerous physiologic processes, including circadian rhythms, mood regulation, anxiety, sleep, appetite, immune responses and cardiac functions. 3,4 Most of the effects of MLT in the brain result from the activation of 2 high-affinity G-protein coupled receptors (GPCRs), MT 1 and MT 2 .5 Of note, GPCRs have a proven history of being excellent therapeutic targets. Recent market analyses indicate that 40%-50% of modern drugs and almost 25% of the top 200 best-selling drugs target GPCRs. 6 In addition to these high-affinity MLT receptors, another low-affinity MLT binding site, MT 3 , has recently been characterized as an MLT-sensitive form of the human enzyme quinone reductase 2. 7 The functional characterization of MT 1 and MT 2 receptors in target tissues is hampered by the paucity of selective MT 1 and MT 2 receptor ligands. Structural Background: Melatonin (MLT) is a pleiotropic neurohormone controlling many physiological processes and whose dysfunction may contribute to several different diseases, such as neurodegenerative diseases, circadian and mood disorders, insomnia, type 2 diabetes and pain. Melatonin is synthesized by the pineal gland during the night and acts through 2 G-protein coupled receptors (GPCRs), MT 1 (MEL1a) and MT 2 (MEL1b). Although a bulk of research has examined the physiopathological effects of MLT, few studies have investigated the selective role played by MT 1 and MT 2 receptors. Here we have reviewed current knowledge about the implications of MT 2 receptors in brain functions. Methods: We searched PubMed, Web of Science, Scopus, Google Scholar and articles reference lists for studies on MT 2 receptor ligands in sleep, anxiety, neuropsychiatric diseases and psychopharmacology, including genetic studies on the MTNR1B gene, which encodes the melatonin MT 2 receptor. Results: These studies demonstrate that MT 2 receptors are involved in the pathophysiology and pharmacology of sleep disorders, anxiety, depression, Alzheimer disease and pain and that selective MT 2 receptor agonists show hypnotic and anxiolytic properties. Limitations: Studies examining the role of MT 2 receptors in psychopharmacology are still limited. Conclusion: The development of novel selective MT 2 receptor ligands, together with further preclinical in vivo studies, may clarify the role of this receptor in brain function and psychopharmacology. The superfamily of GPCRs has proven to be among the most successful drug targets and, consequently, M...

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“…Thus, multiple signaling pathways are mediated by melatonin receptor activation. Focusing on the SCN, both melatonin receptors are involved in regulating the expression of the core clock genes ( Per1 , Per2 , Bmal1 , and Clock ) [26, 36, 37]. Although the circadian machinery is present in every cell, the effect of melatonin on rhythmic clock gene expression is not yet clear.…”

Section: Role Of Melatonin Receptorsmentioning

confidence: 99%

Pathophysiology of Depression: Molecular Regulation of Melatonin Homeostasis – Current Status

Dmitrzak‐Węglarz

Reszka

2017

Neuropsychobiology

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Circadian rhythm alterations resulting in disturbed sleep and disturbed melatonin secretion are flagship features of depression. Melatonin, known as a hormone of darkness, is secreted by the pineal gland located near to the center of the brain between the two hemispheres. Melatonin has an antidepressant effect by maintaining the body’s circadian rhythm, by regulating the pattern of expression of the clock genes in the suprachiasmatic nucleus (SCN) and modifying the key genes of serotoninergic neurotransmission that are linked with a depressive mood. Melatonin is produced via the metabolism of serotonin in two steps which are catalyzed by serotonin N-acetyltransferase (SNAT) and acetylserotonin-O-methyltransferase (ASMT). Serotonin, SNAT, and ASMT are key melatonin level regulation factors. Melatonin acts mainly on the MT₁ and MT₂ receptors, which are present in the SCN, to regulate physiological and neuroendocrine functions including circadian entrainment, referred to as a chronobiotic effect. Although melatonin has been known about and refereed to for almost 50 years, the relationship between melatonin and depression is still not clear. In this review, we summarize current knowledge about the genetic and epigenetic regulation of enzymes involved in melatonin synthesis and metabolism as potential features of depression pathophysiology and treatment. Confirmation that melatonin metabolism in peripheral blood partially reflects a disorder in the brain could be a breakthrough in the standardization of measurements of melatonin level for the development of treatment standards, finding new therapeutic targets, and elaborating simple noninvasive clinical tests.

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The Endogenous Melatonin (MT) Signal Facilitates Reentrainment of the Circadian System to Light-Induced Phase Advances by Acting Upon MT2 Receptors

Cited by 67 publications

References 52 publications

Circadian Rhythm Connections to Oxidative Stress: Implications for Human Health

Circadian Rhythm Connections to Oxidative Stress: Implications for Human Health

Unveiling the role of melatonin MT2 receptors in sleep, anxiety and other neuropsychiatric diseases: a novel target in psychopharmacology

Pathophysiology of Depression: Molecular Regulation of Melatonin Homeostasis – Current Status

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