Melatonin limits transcriptional impact of phosphoCREB in the mouse SCN via the Mel1a receptor.
In the mouse, activity phase-shifts of the endogenous clock in the suprachiasmatic nucleus (SCN) are associated with phosphorylation of the transcription factor Ca2+/cAMP responsive element binding protein (CREB). CREB phosphorylation is induced by the retino-hypothalamic transmitter pituitary adenylate cyclase-activating polypeptide (PACAP). As detected by immunohistochemistry in SCN slices from wild-type mice, melatonin completely blocked PACAP-stimulated CREB phosphorylation at low concentrations (1 nM). In Mel1a melatonin receptor-deficient mice, the PACAP-induced CREB phosphorylation was inhibited only at melatonin concentrations of 100 nM. This inhibition was, however, blunted by blocking the Mel1b melatonin receptor. Thus, melatonin modulates PACAP-mediated retinal stimuli for clock entrainment primarily via the Mel1a melatonin receptor through molecular interaction within the cAMP-signalling pathway.
von Gall
C
C
Dr. Senckenbergische Anatomie, Institute of Anatomy II, Frankfurt, Germany.
Weaver
D R
DR
Kock
M
M
Korf
H W
HW
Stehle
J H
JH
D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D008550:Melatonin / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains / Q000235:genetics; D009479:Neuropeptides / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D009994:Osmolar Concentration; D010766:Phosphorylation / Q000187:drug effects; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000502:physiology*; D044094:Receptors, Melatonin; D012016:Reference Values; D013493:Suprachiasmatic Nucleus / Q000187:drug effects / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*
C495402:Adcyap1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin; D008550:Melatonin