RORα is not a receptor for melatonin (response to DOI 10.1002/bies.201600018)

Slominski, Andrzej; Żmijewski, Michał A.; Jetten, Anton M.

doi:10.1002/bies.201600204

Cited by 50 publications

(44 citation statements)

References 5 publications

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“…Based on these findings, we might conclude that MT2‐mediated cardioprotective actions could be independent of melatonin presence. It is worth noting that although our current study corroborated that the nuclear receptor RORα is an important mediator of melatonin‐conferred cardioprotection, the identity of RORα as a nuclear receptor for melatonin per se was challenged by recent studies . Heretofore, some potent MT2 selective agonists such as IIK7, UCM1014, and DIV0879 have been developed .…”

Section: Discussionmentioning

confidence: 57%

Activation of melatonin receptor 2 but not melatonin receptor 1 mediates melatonin‐conferred cardioprotection against myocardial ischemia/reperfusion injury

Han

Wang

Chen

et al. 2019

Journal of Pineal Research

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Accumulated pieces of evidence have proved the beneficial effects of melatonin on myocardial ischemia/reperfusion (MI/R) injury, and these effects were largely dependent on melatonin membrane receptor activation. In humans and other mammals, there are two types of melatonin receptors, including the melatonin receptor 1 (MT1, melatonin receptor 1a or MTNR1A) and melatonin receptor 1 (MT2, melatonin receptor 1b or MTNR1B) receptor subtypes. However, which receptor mediates melatonin‐conferred cardioprotection remains unclear. In this study, we employed both loss‐of‐function and gain‐of‐function approaches to reveal the answer. Mice (wild‐type; MT1 or MT2 silencing by in vivo minicircle vector; and those overexpressing MT1 or MT2 by in vivo AAV9 vector) were exposed to MI/R injury. Both MT1 and MT2 were present in wild‐type myocardium. MT2, but not MT1, was essentially upregulated after MI/R Melatonin administration significantly reduced myocardial injury and improved cardiac function after MI/R Mechanistically, melatonin treatment suppressed MI/R‐initiated myocardial oxidative stress and nitrative stress, alleviated endoplasmic reticulum stress and mitochondrial injury, and inhibited myocardial apoptosis. These beneficial actions of melatonin were absent in MT2‐silenced heart, but not the MT1 subtype. Furthermore, AAV9‐mediated cardiomyocyte‐specific overexpression of MT2, but not MT1, mitigated MI/R injury and improved cardiac dysfunction, which was accompanied by significant amelioration of oxidative stress, endoplasmic reticulum stress, and mitochondrial dysfunction. Mechanistically, MT2 protected primary cardiomyocytes against hypoxia/reoxygenation injury via MT2/Notch1/Hes1/RORα signaling. Our study presents the first direct evidence that the MT2 subtype, but not MT1, is a novel endogenous cardiac protective receptor against MI/R injury. Medications specifically targeting MT2 may hold promise in fighting ischemic heart disease.

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Section: Discussionmentioning

confidence: 57%

Activation of melatonin receptor 2 but not melatonin receptor 1 mediates melatonin‐conferred cardioprotection against myocardial ischemia/reperfusion injury

Han

Wang

Chen

et al. 2019

Journal of Pineal Research

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“…Moreover, the frequently cited downregulation of 5‐lipoxygenase (5‐LOX) by melatonin, usually interpreted as an antioxidant action, was not confirmed in U937 cells, which instead increased ROS formation via this enzyme, a response that was inhibited by 5‐LOX inhibitors . Additionally, the original interpretation of a mediation of the melatonin effect by the retinoic acid receptor‐related orphan receptor RORα, which was believed to represent a nuclear melatonin receptor, should be dropped, since RORα does not bind melatonin, as has now been convincingly shown . Finally, it should be briefly noted that U937 cells and, especially, their macrophage‐like derivatives are also capable of releasing enhanced levels of the anti‐inflammatory IL‐10, an effect that is only occasionally observed in normal macrophages, but remains to be studied under the influence of melatonin.…”

Section: Proinflammatory Actions As Revealed By Studies On Immune Cellsmentioning

confidence: 98%

“…The role of RORα had been also addressed in the context of NLRP3 inhibition . However, contrary to a rather frequently communicated earlier belief, RORα should no longer be discussed as a nuclear melatonin receptor, since it demonstrably does not bind melatonin . However, this does not exclude indirect actions of melatonin via this transcription factor.…”

Section: Anti‐inflammatory Actions In Medium‐ and High‐grade Inflammamentioning

confidence: 98%

Melatonin and inflammation—Story of a double‐edged blade

Hardeland

2018

Journal of Pineal Research

360

350

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Melatonin is an immune modulator that displays both pro‐ and anti‐inflammatory properties. Proinflammatory actions, which are well documented by many studies in isolated cells or leukocyte‐derived cell lines, can be assumed to enhance the resistance against pathogens. However, they can be detrimental in autoimmune diseases. Anti‐inflammatory actions are of particular medicinal interest, because they are observed in high‐grade inflammation such as sepsis, ischemia/reperfusion, and brain injury, and also in low‐grade inflammation during aging and in neurodegenerative diseases. The mechanisms contributing to anti‐inflammatory effects are manifold and comprise various pathways of secondary signaling. These include numerous antioxidant effects, downregulation of inducible and inhibition of neuronal NO synthases, downregulation of cyclooxygenase‐2, inhibition of high‐mobility group box‐1 signaling and toll‐like receptor‐4 activation, prevention of inflammasome NLRP3 activation, inhibition of NF‐κB activation and upregulation of nuclear factor erythroid 2‐related factor 2 (Nrf2). These effects are also reflected by downregulation of proinflammatory and upregulation of anti‐inflammatory cytokines. Proinflammatory actions of amyloid‐β peptides are reduced by enhancing α‐secretase and inhibition of β‐ and γ‐secretases. A particular role in melatonin's actions seems to be associated with the upregulation of sirtuin‐1 (SIRT1), which shares various effects known from melatonin and additionally interferes with the signaling by the mechanistic target of rapamycin (mTOR) and Notch, and reduces the expression of the proinflammatory lncRNA‐CCL2. The conclusion on a partial mediation by SIRT1 is supported by repeatedly observed inhibitions of melatonin effects by sirtuin inhibitors or knockdown.

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“…Here, we must emphasize that retinoic orphan acid receptor A/α (ROR A/α) is not a receptor for melatonin, an error that is frequently repeated by melatonin researchers. It is a receptor for sterols, oxysterols, and secosteroids [33, 50, 51]. …”

Section: Physiological Role Of Melatonin and Metabolites In The Skinmentioning

confidence: 99%

Melatonin, mitochondria, and the skin

Słomiński

Żmijewski

Semak

et al. 2017

Cell. Mol. Life Sci.

Self Cite

166

146

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The skin being a protective barrier between external and internal (body) environments has the sensory and adaptive capacity to maintain local and global body homeostasis in response to noxious factors. An important part of the skin response to stress is its ability for melatonin synthesis and subsequent metabolism through the indolic and kynuric pathways. Indeed, melatonin and its metabolites have emerged as indispensable for physiological skin functions and for effective protection of a cutaneous homeostasis from hostile environmental factors. Moreover, they attenuate the pathological processes including carcinogenesis and other hyperproliferative/inflammatory conditions. Interestingly, mitochondria appear to be a central hub of melatonin metabolism in the skin cells. Furthermore, substantial evidence has accumulated on the protective role of the melatonin against ultraviolet radiation and the attendant mitochondrial dysfunction. Melatonin and its metabolites appear to have a modulatory impact on mitochondrion redox and bioenergetic homeostasis, as well as the anti-apoptotic effects. Of note, some metabolites exhibit even greater impact than melatonin alone. Herein, we emphasize that melatonin–mitochondria axis would control integumental functions designed to protect local and perhaps global homeostasis. Given the phylogenetic origin and primordial actions of melatonin, we propose that the melatonin-related mitochondrial functions represent an evolutionary conserved mechanism involved in cellular adaptive response to skin injury and repair.

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RORα is not a receptor for melatonin (response to DOI 10.1002/bies.201600018)

Cited by 50 publications

References 5 publications

Activation of melatonin receptor 2 but not melatonin receptor 1 mediates melatonin‐conferred cardioprotection against myocardial ischemia/reperfusion injury

Activation of melatonin receptor 2 but not melatonin receptor 1 mediates melatonin‐conferred cardioprotection against myocardial ischemia/reperfusion injury

Melatonin and inflammation—Story of a double‐edged blade

Melatonin, mitochondria, and the skin

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