Mechanisms of RORα-dependent effects of melatonin

Abstract

The transcription factor RORα has not traditionally been attributed a fundamental role in the development of Th17 cells, but recent studies have shown that it is necessary for the formation of a pathogenic variant of Th17 cells, the so-called Th1-polarized Th17 (Th17.1). Since the transcriptional activity of RORα depends on ligand binding, the search for such ligands is highly relevant, and in this regard, melatonin is of particular interest. The question of the ability of RORα to directly bind melatonin remains open today; data on this problem are extremely contradictory. In 1995, I. Wiesenberg and colleagues identified RORα as a nuclear receptor for melatonin, demonstrating the hormone’s ability to enhance the binding of this factor to DNA and determining the dissociation constant for the interaction of RORα with melatonin using classical Scatchard analysis. In 2011, P.J. Lardone and colleagues “rediscovered” RORα as a receptor for melatonin by demonstrating the coprecipitation of melatonin with RORα. And in 2016, A.J. Slominski and colleagues published a paper that cast doubt on the possibility of melatonin binding to RORα based on molecular modeling of ligand-receptor interactions supported by functional studies. However, a careful analysis of these data indicates the ambiguity of this conclusion, allowing us to speak, rather, of medium or low binding affinity of the hormone to RORα, but not of its absence. This conclusion is also supported by the fact that RORα mediates many of the effects of melatonin, both physiological and pharmacological, including the regulation of circadian rhythms and oxidative metabolism, neuro- and cardioprotection, and control of the immune response. In general, the data available today allow us to consider the transcription factor RORα as a receptor for melatonin with medium affinity, although indirect regulation of this factor by the hormone is not excluded, and RORα-dependent mechanisms should contribute to the cellular response to melatonin, both under physiological conditions and in the case of pharmacological use of the hormone.