Mechanisms Regulating Melatonin Synthesis in the Mammalian Pineal Organ
- 1 December 2005
- journal article
- Published by Wiley in Annals of the New York Academy of Sciences
- Vol. 1057 (1), 372-383
- https://doi.org/10.1196/annals.1356.028
Abstract
The day/night rhythm in melatonin production is a characteristic feature in vertebrate physiology. This hormonal signal reliably reflects the environmental light conditions and is independent of behavioral aspects. In all mammalian species, melatonin production is regulated by norepinephrine, which is released from sympathetic nerve fibers exclusively at night. Norepinephrine elevates the intracellular cAMP concentration via beta-adrenergic receptors and activates the cAMP-dependent protein kinase A. This pathway is crucial for regulation of the penultimate enzyme in melatonin biosynthesis, the arylalkylamine N-acetyltransferase (AANAT); cAMP/protein kinase A may, however, act in different ways. In ungulates and primates, pinealocytes constantly synthesize AANAT protein from continually available Aanat mRNA. During the day-in the absence of noradrenergic stimulation-the protein is immediately destroyed by proteasomal proteolysis. At nighttime, elevated cAMP levels cause phosphorylation of AANAT by protein kinase A. This posttranslational modification leads to interaction of phosphorylated AANAT with regulatory 14-3-3 proteins, which protect AANAT from degradation. Increases in AANAT protein are paralleled by increases in enzyme activity. Stimulation of the cAMP/protein kinase A pathway may also activate pineal gene expression. In rodents, transcriptional activation of the Aanat gene is the primary mechanism for the induction of melatonin biosynthesis and results in marked day/night fluctuations in Aanat mRNA. It involves protein kinase A-dependent phosphorylation of the transcription factor cyclic AMP response element-binding protein (CREB) and binding of phosphorylated CREB in the promoter region of the Aanat gene. In conclusion, a common neuroendocrine principle, the nocturnal rise in melatonin, is controlled by strikingly diverse regulatory mechanisms. This diversity has emerged in the course of evolution and reflects the high adaptive plasticity of the melatonin-generating pineal organ.Keywords
This publication has 60 references indexed in Scilit:
- Dephosphorylation of pCREB by protein serine/threonine phosphatases is involved in inactivation of Aanat gene transcription in rat pineal glandJournal of Neurochemistry, 2003
- Norepinephrine-dependent phosphorylation of the transcription factor cyclic adenosine monophosphate responsive element-binding protein in bovine pinealocytesJournal of Pineal Research, 2003
- Coordination of circadian timing in mammalsNature, 2002
- The anatomy and innervation of the mammalian pineal glandCell and tissue research, 2002
- Output pathways of the mammalian suprachiasmatic nucleus: coding circadian time by transmitter selection and specific targetingCell and tissue research, 2002
- Neurotransmitters of the retino-hypothalamic tractCell and tissue research, 2002
- Orphan Nuclear Receptor RZRβ : Cyclic AMP Regulates Expression in the Pineal GlandBiochemical and Biophysical Research Communications, 1996
- Calcium responses of isolated, immunocytochemically identified rat pinealocytes to noradrenergic, cholinergic and vasopressinergic stimulationsNeurochemistry International, 1995
- Calcium Potentiates Cyclic AMP Stimulation of Pineal Arylalkylamine N‐AcetyltransferaseJournal of Neurochemistry, 1993
- Phorbol Esters Mimic α‐Adrenergic Potentiation of Serotonin N‐Acetyltransferase Induction in the Rat PinealJournal of Neurochemistry, 1985