Melatonin and retinoid orphan receptors: Demand for new interpretations after their exclusion as nuclear melatonin receptors

Abstract

The demonstrated incapability of the retinoic acid receptor-related orphan receptor-α (RORα) to bind melatonin inevitably requires consequences for interpreting numerous reports on actions of this protein as far as it was believed to be a nuclear melatonin receptor. While the synthetic compound CGP 52608 is, in fact, a ligand of RORα, effects obtained with this molecule can no longer be attributed to melatonin. Moreover, the sometimes assumed interplay between melatonin membrane receptors and RORα as nuclear receptors has to be dropped. Conclusions on melatonin’s actions via RORα that were based on a lack of demonstrable involvement of membrane receptors appear to have been precocious. Nevertheless, findings on melatonin uptake into the nucleus may still be taken as a hint for nuclear melatonin receptors, but this would require thorough characterization. Although RORα does not bind melatonin, it is interrelated to the latter in regulatory terms by involvement of cellular circadian oscillators. A mode of action seems to be the upregulation of sirtuin-1 by melatonin, deacetylation of poly ADP ribose polymerase-γ coactivator-1α (PGC-1α) by sirtuin-1, and facilitation of RORα binding to its response element by deacetylated PGC-1α, a route that had been shown to exist in circadian oscillators, thereby enhancing their amplitude.