Pineal gland hormone melatonin binds and activates an orphan of the nuclear receptor superfamily.

Abstract

Nuclear orphan receptors are members of the superfamily of structurally related, ligand-inducible transcription factors for which no ligand has yet been identified.Over the past few years many nuclear orphan receptors have been cloned, but only for the retinoid X receptor (RXR) has a natural ligand (9-cis-retinoic acid) been found.Here we report the identification of melatonin as a ligand for the recently cloned orphan receptor retinoid Z receptor P (RZRP).W e found RZRP expression in the rat brain nearly coincident with binding sites for the pineal gland hormone melatonin (6-methoxy-Nacetyltryptamine).W e show here binding and activation of RZRP by melatonin with Kd and EC, values in the low nanomolar range.A nuclear signaling pathway for melatonin may contribute to some of the diverse and profound effects of this hormone, for example, in the context of circadian rhythmicity.In vertebrates the hormone melatonin plays an important role as a transmitter of photoperiodic information and regulator of seasonal reproductive cycles.It is secreted primarily from the pineal gland and the retina during the hours of darkness (1).Binding sites for melatonin with Kd values in the picomolar range have been identified in membrane preparations of various tissues and cell lines (1-3).Recently, a protein with seventransmembrane-spanning hydrophobic domains was identified as the membrane receptor for melatonin with a Kd value of 63 Previous studies have shown a nuclear localization of melatonin in different mammalian tissues, suggesting that melatonin may have a function on the nuclear level in these tissues (5, 6).Furthermore, very recently specific melatonin binding sites in rat liver cell nuclei have been described and characterized pM (4).