Institut für Physiologische Chemie I, Heinrich-Heine-Universität, Düsseldorf, Germany
The physiological and neuroendocrine functions of the pineal
gland hormone, melatonin, and its therapeutic potential critically
depend on the understanding of its target sites and its mechanisms
of action. This has progressed considerably in the last few
years through the cloning of G protein-coupled seven-transmembrane
melatonin receptors (Mel
1a and Mel
1b) as well as of nuclear
receptors (RZR/ROR
and RZRß) that are associated with
melatonin signaling. The transcription factor RZR/ROR
appears
to mediate a direct gene regulatory action of the hormone, and
specific binding sites have been identified in promoter regions
of a variety of genes, such as 5-lipoxygenase (5-LO), p21
WAF1/CIP1,
and bone sialoprotein (BSP). The membrane signaling pathway
clearly shows higher ligand sensitivity than the nuclear signaling
pathway, but details of its signal transduction cascade, and
target genes are presently unknown. Membrane melatonin receptors
are expressed mainly in the central nervous system, whereas
RZR/ROR
is prominently expressed both in the periphery and the
brain. The action of membrane melatonin receptors and their
specific agonists have been associated with circadian rhythmicity,
whereas direct effects of melatonin in the periphery, such as
immunomodulation, cellular growth, and bone differentiation,
mainly appear to be mediated by RZR/ROR
. It is hypothesized
in this review that, in some cases, RZR/ROR
may be a primary
target of membrane melatonin receptors.
