TRANSCRIPTIONAL ACTIVATION OF THE NUCLEAR RECEPTOR RZR-ALPHA BY THE PINEAL-GLAND HORMONE MELATONIN AND IDENTIFICATION OF CGP-52608 AS A SYNTHETIC LIGAND

Many important physiological functions are controlled by hormones via binding and activating members of the nuclear receptor superfamily. Th is 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 t o understanding their physiological role, as has been successfully sho wn for retinoid X receptors and the discovery of 9-cis retinoic acid a s a specific ligand. We have discovered very recently that the pineal gland hormone melatonin is a specific ligand for the brain-specific nu clear receptor RZR beta. Here we report that the alpha-subtype of RZR, RZR alpha and its splicing variant ROR alpha 1, is also a nuclear rec eptor for melatonin with binding specificities in the low nanomolar ra nge. In contrast to RZR beta, RZR/ROR alpha is expressed in many tissu es and cells outside the brain. We found that RZR alpha and ROR alpha 1 vary in their constitutive transactivational activity and are activa ted to a different extent by melatonin. Furthermore, we Identified a s ynthetic RZR-ligand, the thiazolidine dione CGP 52608. This compound i s a functional analogue of melatonin at its nuclear receptor, but does not bind to the high affinity membrane receptor for melatonin. Theref ore, this specific RZR-ligand may help to differentiate between nuclea r and membrane signalling of melatonin.