Interaction of melatonin and Bmal1 in the regulation of PI3K/AKT pathway components and cellular survival

Abstract

The circadian rhythm is driven by a master clock within the suprachiasmatic nucleus which regulates the rhythmic secretion of melatonin. Bmal1 coordinates the rhythmic expression of transcriptome and regulates biological activities, involved in cell metabolism and aging. However, the role of Bmal1 in cellular- survival, signaling, its interaction with intracellular proteins, and how melatonin regulates its expression is largely unclear. Here we observed that melatonin increases the expression of Bmal1 and both melatonin and Bmal1 increase cellular survival after oxygen glucose deprivation (OGD) while the inhibition of Bmal1 resulted in the decreased cellular survival without affecting neuroprotective effects of melatonin. By using a planar surface immunoassay for PI3K/AKT signaling pathway components, we revealed that both melatonin and Bmal1 increased phosphorylation of AKT, ERK-1/2, PDK1, mTOR, PTEN, GSK-3αβ, and p70S6K. In contrast, inhibition of Bmal1 resulted in decreased phosphorylation of these proteins, which the effect of melatonin on these signaling molecules was not affected by the absence of Bmal1. Besides, the inhibition of PI3K/AKT decreased Bmal1 expression and the effect of melatonin on Bmal1 after both OGD in vitro and focal cerebral ischemia in vivo. Our data demonstrate that melatonin controls the expression of Bmal1 via PI3K/AKT signaling, and Bmal1 plays critical roles in cellular survival via activation of survival kinases.

The Rhythmicity of Clock Genes is Disrupted in the Choroid Plexus of the APP/PS1 Mouse Model of Alzheimer’s Disease

“…Melatonin actions were also reflected in the recovery of the phase relationship between Bmal1 and Per2 in rat adrenal cultures [57]. Recently, it was shown that melatonin controls the expression of Bmal1 through PI3K/AKT signaling [58]. Thus, our results point to the relevance of the potential modulatory effect of melatonin in the circadian clock of CP epithelial cells, which are known to express melatonin receptors (MT1 and MT2) [59] and to be involved in the chronobiotic action of melatonin [60].…”

Physiological and pharmacological roles of melatonin in the pathophysiological components of cellular injury after ischemic stroke

“…In this term, we have indicated that tolerance to ischemic injury changes according to the time of day in which the injury occurs and the underlying mechanism of this tolerance includes circadian clock genes, specifically Bmal1, which is also regulated by the phosphorylation of AKT signaling pathway [24]. Consistently, Bmal1 expression is enhanced following melatonin treatment following ischemic brain injury in mice and this increase is blocked when the survival kinase AKT inhibitors are present [26]. In addition to the transcriptional control of Bmal1 gene, melatonin may also regulate clock genes by stabilizing the protein through the inhibition of the ubiquitin-proteasome system [28].…”

“…Of these genes, the six core clock genes are known as Per1 and Per2, Cry1 and Cry2, Clock and Bmal1 [24,25]. We have reported that melatonin regulates Bmal1 expression under normal conditions in vitro after hypoxia and in vivo after ischemic stroke [26]. Interestingly, in parallel with the highest blood concentrations of melatonin, the ischemic stroke incidence is lowest at the midnight hours in human [27].…”

Melatonin and Autophagy in Aging-Related Neurodegenerative Diseases

“…Previous studies observed that the Akt was significantly phosphorylated 2 h after melatonin treatment, and its phosphorylation lasted for up to 24 h. The expression of glial-cell-line-derived neurotrophic factor (GDNF) in the CA3 area was significantly increased after 6 h of melatonin treatment. After 24 h, the GDNF was mainly secreted by astrocytes [ 248 , 249 ].…”