Abstract

Many important physiological functions are controlled by hormones via binding and activating members of the nuclear receptor superfamily. This group of structurally related transcription factors also includes a still growing number of orphan receptors for which no ligand is known so far. The identification of ligands for orphan receptors is a key to understanding their physiological role, as has been successfully shown for retinoid X receptors and the discovery of 9- cis retinoic acid as a specific ligand. We have discovered very recently that the pineal gland hormone melatonin is a specific ligand for the brain-specific nuclear receptor RZRβ. Here we report that the α-subtype of RZR, RZRα and its splicing variant RORα1, is also a nuclear receptor for melatonin with binding specificities in the low nanomolar range. In contrast to RZRβ, RZR/RORα is expressed in many tissues and cells outside the brain. We found that RZRα and RORα1 vary in their constitutive transactivational activity and are activated to a different extent by melatonin. Furthermore, we identified a synthetic RZR-ligand, the thiazolidine dione CGP 52608. This compound is a functional analogue of melatonin at its nuclear receptor, but does not bind to the high affinity membrane receptor for melatonin. Therefore, this specific RZR-ligand may help to differentiate between nuclear and membrane signalling of melatonin.

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