ROR: Nuclear Receptor for Melatonin or Not?

Abstract

Whether the retinoic acid-related orphan receptor (ROR) is a nuclear receptor of melatonin remains controversial. ROR is inextricably linked to melatonin in terms of its expression, function, and mechanism of action. Additionally, studies have illustrated that melatonin functions analogous to ROR ligands, thereby modulating the transcriptional activity of ROR. However, studies supporting these interactions have since been withdrawn. Furthermore, recent crystallographic evidence does not support the view that ROR is a nuclear receptor of melatonin. Some other studies have proposed that melatonin indirectly regulates ROR activity rather than directly binding to ROR. This review aims to delve into the complex relationship of the ROR receptor with melatonin in terms of its structure, expression, function, and mechanism. Thus, we provide the latest evidence and views on direct binding as well as indirect regulation of ROR by melatonin, dissecting both viewpoints in-depth to provide a more comprehensive perspective on this issue.

Revisiting the role of melatonin in human melanocyte physiology: A skin context perspective

“…It has been clarified that melatonin and its metabolites are not ligands for the nuclear receptor retinoid‐related orphan receptor‐α (ROR‐α aka NR1F1), as shown by crystallography studies, 108,109 modeling and receptor functional assays 110 . However, melatonin may indirectly modulate ROR‐α and other ROR activities 109,111 …”

“…110 However, melatonin may indirectly modulate ROR-α and other ROR activities. 109,111 Moreover, facilitated by their dendritic morphology, which greatly augments their cell surface and thus contact area, melanocytes operate as multimodal sensory and stress-response cells. [112][113][114][115][116] Melanocytes also engage in bidirectional communication with their tissue-specific intraepithelial habitat, 112 for example, by secreting catecholamines, cytokines, eicosanoids, acetylcholine, melanocortins, ACTH, CRH, endorphins, enkephalins, nitric oxide, serotonin, and reactive oxygen species (ROS) produced during melanogenesis.…”

Use of Melatonin in Cancer Treatment: Where Are We?

“…These biological effects are linked with an array of molecular mechanisms such as binding to membrane receptors, interacting with cytosolic and nuclear proteins, and scavenging radicals directly. Three distinct classes of putative melatonin receptors were reported: (1) MTNR1A (MT1) and MTNR1B (MT2), two membrane receptors of melatonin belonging to the G-protein-coupled receptors’ superfamily [ 17 ]; (2) retinoid orphan receptors (ROR), members of the steroid receptor superfamily, which are thought to be the nuclear receptor of melatonin [ 18 ], although this concept remains controversial [ 19 ]; and (3) the third melatonin binding site MT3, which is identified as quinone reductase 2 [ 20 ]. Activation of either MT1 or MT2 by melatonin results in the decreased cyclic adenosine monophosphate (cAMP) and, thus, leads to the inhibition of protein kinase A (PKA) activity.…”

Melatonin and cancer suppression: insights into its effects on DNA methylation

“…These biological properties have a broad spectrum of molecular mechanisms, including binding to receptors of cell membranes, interacting with different proteins in cytosol and nucleus, and direct scavenging of free radicals such as ROSs [ 1 ]. Three different classes of putative receptors for melatonin have been characterized: in the membrane, MT1 and MT2 are members of the superfamily of G-protein-coupled receptors which are encoded by MTNR1A and MTNR1B, respectively, [ 19 ]; retinoid orphan receptors (RORs), located in the nucleus, belong to the steroid receptor superfamily; they have been shown to bind melatonin [ 20 , 21 ]; finally, the MT3 melatonin binding site, also is known as quinone reductase 2 (QR2), is situated in the cytosol [ 22 ]. Melatonin-induced activation of either MT1 or MT2 receptors causes decreased activity of adenylyl cyclase and, subsequently, reduced levels of cyclic adenosine monophosphate (cAMP); this leads to protein kinase A (PKA) activity repression.…”