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. 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 RZR beta. Here we report that the alpha-subtype of RZR, RZR alpha and its splicing variant ROR alpha 1, is also a nuclear receptor for melatonin with binding specificities in the low nanomolar range. In contrast to RZR beta, RZR/ROR alpha is expressed in many tissues and cells outside the brain. We found that RZR alpha and ROR alpha 1 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.
Wiesenberg
I
I
Pharma-Forschung, Ciba-Geigy AG, Basel, Switzerland.
Missbach
M
M
Kahlen
J P
JP
Schräder
M
M
Carlberg
C
C
D000818:Animals; D001483:Base Sequence; D001667:Binding, Competitive; D002460:Cell Line; D004330:Drosophila; D007700:Kinetics; D008024:Ligands; D008550:Melatonin / Q000378:metabolism / Q000494:pharmacology*; D008969:Molecular Sequence Data; D011956:Receptors, Cell Surface / Q000378:metabolism* / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism* / Q000502:physiology; D044094:Receptors, Melatonin; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology*; D013882:Thiosemicarbazones / Q000378:metabolism / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects*; D014162:Transfection
D008024:Ligands; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin; D013844:Thiazoles; D013882:Thiosemicarbazones; C092451:CGP 52608; D008550:Melatonin