The potential role of the transcription factor RZR/ROR as a mediator of nuclear melatonin signaling

The pineal gland hormone melatonin is well known as a regulator of circadia n rhythmicity, but has also other functions in the central nervous system a s well as in the periphery including the maturation of neurons and the regu lation of cellular growth and differentiation. Three mechanisms of the horm one's action are currently discussed: a membrane signaling pathway, a nucle ar signaling pathway and a receptor-independent radical scavenging function . Melatonin membrane receptors are seven transmembrane receptors and mediat e their functions through a G-protein-coupled second messenger pathway. Nuc lear melatonin signaling seems to be mediated via the transcription factor RZR/ROR, which is an orphan member of the nuclear receptor superfamily. The widespread distribution of the a-subtype of RZR/ROR suggests that this rec eptor may be an important mediator of those effects of melatonin that can n ot be explained by membrane receptors or radical scavenging. Interestingly, natural RZR/ROR alpha "knock-out" mice (staggerer) show severe defects in the development of cerebellar Purkinje cells, a reduced body weight and imm unological defects. RZR/ROR binds as a monomer to DNA, but also forms homod imers on appropriate binding sites. Natural RZR/ROR binding sites have been identified in the regulatory regions of many genes. 5-lipoxygenase, p21(WA F1/CIP1), apolipoprotein A-I, N-myc and Purkinje cell protein 2 may be func tionally important target genes. On some of these binding sites RZR/ROR com petes with other members of the nuclear receptor superfamily (e.g., COUP-TF , RAR and Rev-ErbA) indicating a cross-talk between these transcription fac tors. RZR/ROR often shows in transient transfection assays a high constitut ive, i.e. ligand-independent activity. However, under conditions of low con stitutive activity a significant and specific stimulation of RZR/ROR by low nanomolar concentrations of melatonin and a structurally novel class of th iazolidinediones (lead structure: CGP52608) has been observed. Taken togeth er, the effects of melatonin on transcriptional regulation clearly depend o n the expression of RZR/ROR and support the concept that the receptor is a mediator of nuclear melatonin signaling.