Melatonin Signal Transduction Pathways Require E-Box-Mediated Transcription of Per1 and Per2 to Reset the SCN Clock at Dusk

Abstract

Melatonin is released from the pineal gland into the circulatory system at night in the absence of light, acting as “hormone of darkness” to the brain and body. Melatonin also can regulate circadian phasing of the suprachiasmatic nucleus (SCN). During the day-to-night transition, melatonin exposure advances intrinsic SCN neural activity rhythms via the melatonin type-2 (MT2) receptor and downstream activation of protein kinase C (PKC). The effects of melatonin on SCN phasing have not been linked to daily changes in the expression of core genes that constitute the molecular framework of the circadian clock. Using real-time RT-PCR, we found that melatonin induces an increase in the expression of two clock genes, Period 1 (Per1) and Period 2 (Per2). This effect occurs at CT 10, when melatonin advances SCN phase, but not at CT 6, when it does not. Using anti-sense oligodeoxynucleotides (α ODNs) to Per 1 and Per 2, as well as to E-box enhancer sequences in the promoters of these genes, we show that their specific induction is necessary for the phase-altering effects of melatonin on SCN neural activity rhythms in the rat. These effects of melatonin on Per1 and Per2 were mediated by PKC. This is unlike day-active non-photic signals that reset the SCN clock by non-PCK signal transduction mechanisms and by decreasing Per1 expression. Rather, this finding extends roles for Per1 and Per2, which are critical to photic phase-resetting, to a nonphotic zeitgeber, melatonin, and suggest that the regulation of these clock gene transcripts is required for clock resetting by diverse regulatory cues.

Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics

“…PER1/2 are well known to be regulated by melatonin [179,180]. For example, melatonin induces a rise in the expression of PER1/2 [181]. The regulation of PER1/2 by melatonin not only occurs centrally in the suprachiasmatic nucleus (SCN) but also peripherally, that is, it occurs in peripheral cells [182].…”

Impact of Melatonin on Skeletal Muscle and Exercise

“…Molecular mechanisms regulating circadian rhythms, clock genes, and transcriptional regulators were firstly characterized in Drosophila and then extended to higher organisms [163]. Compelling evidence indicates that there is another peripheral clock in skeletal muscle crucial for the maintenance of mitochondrial balance, muscle metabolism, and energy in sarcopenia [164][165][166][167].…”

Pathophysiology of Depression: Molecular Regulation of Melatonin Homeostasis – Current Status

“…The regulation of circadian rhythm by melatonin acts via specific receptors located at a high density in the SCN [26-28]. This effect is mediated by two types of melatonin receptors, well characterized in mammals by Dubocovich et al [29].…”

“…Thus, multiple signaling pathways are mediated by melatonin receptor activation. Focusing on the SCN, both melatonin receptors are involved in regulating the expression of the core clock genes ( Per1 , Per2 , Bmal1 , and Clock ) [26, 36, 37]. Although the circadian machinery is present in every cell, the effect of melatonin on rhythmic clock gene expression is not yet clear.…”