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 However, studies supporting these interactions have since been withdrawn.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.
Highlights
Whether the retinoic acid-related orphan receptor (ROR) is a nuclear receptor of melatonin remains controversial
As a ligand-dependent transcription factor, ROR modulates the transcription of target genes by binding to ROR response elements (RORE) present in the target genes
In 1993, melatonin was detected in the nuclei of cells, which led to the inference of the presence of melatonin’s nuclear receptors [9,18,19]
Summary
In 1993, melatonin was detected in the nuclei of cells, which led to the inference of the presence of melatonin’s nuclear receptors [9,18,19]. The ROR group includes three members: RORα (RORA, NR1F1, or RZRα), RORβ (RORB, NR1F2, or RZRβ), and RORγ (RORC or NR1F3) [20]. Four RORα isoforms (RORα1–4) have been identified in humans, whereas only two have been reported in mice (RORα1 and RORα4). Murine expression of the RORβ1 and RORβ2 isoforms have been reported, but only the RORβ1 isoform has been identified in humans. Both humans and mice express RORγ1 and RORγ2 (RORγ2 is known as RORγt). The expression patterns for the three members of the ROR group varies, and some isoforms appear to be tissue-specific. RORγ1 expression is prevalent in the muscles, adipose tissue, liver, and kidneys, similar to RORα [24]. RORγt, known as the thymic isoform, is confined to certain immune cells, such as group 3 innate lymphoid cells (ILC3) [25] and T helper 17 (Th17) cells [26]
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