Endogenous melatonin provides an effective circadian message to both the suprachiasmatic nuclei and the pars tuberalis of the rat

Abstract

The suprachiasmatic nuclei (SCN) distribute the circadian neural message to the pineal gland which transforms it into a humoral circadian message, the nocturnal melatonin synthesis, which in turn modulates tissues expressing melatonin receptors such as the SCN or the pars tuberalis (PT). Nuclear orphan receptors (NOR), including rorbeta and rev-erbalpha, have been presented as functional links between the positive and negative loops of the molecular clock. Recent findings suggest that these NOR could be the initial targets of melatonin's chronobiotic message within the SCN. We investigated the role of these NOR in the physiological effect of endogenous melatonin on these tissues. We monitored rorbeta and rev-erbalpha mRNA expression levels by quantitative in situ hybridization after pinealectomy. Pinealectomy had no effect on NOR circadian expression rhythms in the SCN in 8-day pinealectomized (PX) animals. However in animals PX for 3 months, significant desynchronization between per1 and per2 transcription patterns appeared. These results suggest that endogenous melatonin could sustain the circadian rhythmicity and the phase relationship between the molecular partners of the SCN circadian system on a long-term basis. On the other hand, pinealectomy decreased the level and abolished the rhythmicity of NOR mRNA expression in the PT. These effects were partially prevented by daily melatonin administration in the drinking water. These results show that NOR can be regulated by the melatonin circadian rhythm in the PT and could be the link between the physiological action of melatonin and the core of the molecular circadian clock in this tissue.

Melatonin replacement restores the circadian behavior in adult rat Leydig cells after pinealectomy

“…The cAMP signaling can acutely induce Per1 expression through CRE/CREB (Travnickova-Bendova et al, 2002;Doi et al, 2011). MNTR1A knockout and pinealectomized mice studies support that MNTR1A-mediated melatonin signaling is important for circadian rhythms and the expression levels of several clock genes including Per1, Cry1, and Rev-erba in cells of pars tubularis (Agez et al, 2009). This observation is in agreement with the increased Per1/2 in LCs after pinealectomy.…”

Genetic suppression of the circadian Clock mutation by the melatonin biosynthesis pathway

“…The effect of melatonin on phase shifting of the circadian rhythm in the SCN is mediated through protein kinase C activation (36). Although some studies report that melatonin can affect clock gene expression in the SCN (37)(38)(39), the signal transduction pathway from melatonin to the core clock remains to be defined. Interestingly, protein kinase C-mediated phosphorylation of CLOCK has been implicated in the resetting of circadian rhythms (40), and RACK1 and protein kinase Cα have been shown to interact with BMAL1 in a circadian manner (41).…”

An insight into the scientific background and future perspectives for the potential uses of melatonin

“…Regulation of pineal melatonin biosynthesis is largely explained by control mechanisms acting on arylalkylamine N-acetyltransferase, at the levels of gene expression and/or enzyme stability influenced by phosphorylation and interaction with 14-3-3 proteins [126]. Further, it has been suggested that nuclear orphan receptors (NOR) can be regulated by the melatonin circadian rhythm in the pars tuberalis (PT) and could be the link between the physiological action of melatonin and the core of the molecular circadian clock in this tissue [127].…”