Affiliations: Pharma Research, NOVARTIS, Basel, Switzerland | Institut für Physiologische Chemie I,
Heinrich-Heine-Universität, Düsseldorf, Germany
Abstract: The pineal gland hormone melatonin is well known as a regulator of
circadian rhythmicity, but has also other functions in the central nervous
system as well as in the periphery including the maturation of neurons and the
regulation of cellular growth and differentiation. Three mechanisms of the
hormone's action are currently discussed: a membrane signaling pathway, a
nuclear signaling pathway and a receptor-independent radical scavenging
function. Melatonin membrane receptors are seven transmembrane receptors and
mediate their functions through a G-protein-coupled second messenger pathway.
Nuclear 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 receptor
may be an important mediator of those effects of melatonin that can not be
explained by membrane receptors or radical scavenging. Interestingly, natural
RZR/RORa "knock-out" mice (staggerer) show severe defects in the development of
cerebellar Purkinje cells, a reduced body weight and immunological defects.
RZR/ROR binds as a monomer to DNA, but also forms homodimers on appropriate
binding sites. Natural RZR/ROR binding sites have been identified in the
regulatory regions of many genes. 5-lipoxygenase, p21WAF1/CIP1, apolipoprotein
A-1, N-myc and Purkinje cell protein 2 may be functionally important target
genes. On some of these binding sites RZR/ROR competes with other members of
the nuclear receptor superfamily (e.g., COUP-TF, RAR and Rev-ErbA) indicating a
cross-talk between these transcription factors RZR/ROR often shows in transient
transfection assays a high constitutive, i.e. ligand-independent activity.
However, under conditions of low constitutive activity a significant and
specific stimulation of RZR/ROR by low nanomolar concentrations of melatonin
and structurally novel class of thiazolidinediones (lead structure: CGP52608)
has been observed. Taken together, the effects of melatonin on transcriptional
regulation clearly depend on the expression fo RZR/ROR and support the concept
that the receptor is a mediator of nuclear melatonin signaling.
Keywords: melatonin, nuclear signaling, nuclear receptor RZR/ROR, natural responding genes, thaizolidinediones, regulation of transcription, interference with membrane receptors
