Adenosine triphosphate (ATP) is released onto the pinealocyte, along with noradrenaline, from sympathetic neurons and triggers P2Y1 receptors that enhance β-adrenergic-induced N-acetylserotonin (NAS) synthesis. Nevertheless, the biotransformation of NAS into melatonin, which occurs due to the subsequent methylation by acetylserotonin O-methyltransferase (ASMT; EC 2.1.1.4), has not yet been evaluated in the presence of purinergic stimulation. We therefore evaluated the effects of purinergic signaling on melatonin synthesis induced by β-adrenergic stimulation. ATP increased NAS levels, but, surprisingly, inhibited melatonin synthesis in an inverse, concentration-dependent manner. Our results demonstrate that enhanced NAS levels, which depend on phospholipase C (PLC) activity (but not the induction of gene transcription), are a post-translational effect. By contrast, melatonin reduction is related to an ASMT inhibition of expression at both the gene transcription and protein levels. These results were independent of nuclear factor-kappa B (NF-kB) translocation. Neither the P2Y1 receptor activation nor the PLC-mediated pathway was involved in the decrease in melatonin, indicating that ATP regulates pineal metabolism through different mechanisms. Taken together, our data demonstrate that purinergic signaling differentially modulates NAS and melatonin synthesis and point to a regulatory role for ATP as a cotransmitter in the control of ASMT, the rate-limiting enzyme in melatonin synthesis. The endogenous production of melatonin regulates defense responses; therefore, understanding the mechanisms involving ASMT regulation might provide novel insights into the development and progression of neurological disorders since melatonin presents anti-inflammatory, neuroprotective, and neurogenic effects.
Daily oscillation of the immune system follows the central biological clock outputs control such as melatonin produced by the pineal gland. Despite the literature showing that melatonin is also synthesized by macrophages and t lymphocytes, no information is available regarding the temporal profile of the melatonergic system of immune cells and organs in steady-state. Here, the expression of the enzymes arylalkylamine-n-acetyltransferase (AA-nAt), its phosphorylated form (p-AA-nAt) and acetylserotonin-O-methyltransferase (ASMT) were evaluated in phagocytes and T cells of the bone marrow (BM) and spleen. We also determined how the melatonergic system of these cells is modulated by LPS and the cytokine IL-10. The expression of the melatonergic enzymes showed daily rhythms in BM and spleen cells. Melatonin rhythm in the BM, but not in the spleen, follows P-AA-NAT daily variation. In BM cells, LPS and IL10 induced an increase in melatonin levels associated with the increased expressions of P-AA-NAT and ASMT. In spleen cells, LPS induced an increase in the expression of P-AA-NAT but not of melatonin. Conversely, IL10 induced a significant increase in melatonin production associated with increased AA-NAT/P-AA-NAT expressions. In conclusion, BM and spleen cells present different profiles of circadian production of local melatonin and responses to immune signals.Organs and cells of the immune system present daily variations regulated by oscillators present in each cell 1-6 . The intrinsic circadian clock of most of the immune cells imposes circadian expression of downstream genes and functions 4 . This is the case for the expression of pattern-recognition receptors and cytokines, the recruitment to tissues and the phagocytic activity of monocytes, macrophages and microglia 7-10 . Clock genes are also circadian expressed in mouse lymph nodes 10,11 and in B splenic cells 12 , where they control the activity of the cells 4,11 . Besides the intrinsic rhythmicity of cells and organs, there is a central synchronization that relies on neural and hormonal signaling controlled by the central clock in the suprachiasmatic nuclei 13,14 . After a sympathetic input, the darkness hormone melatonin, prolactin and glucocorticoids impose, for example, a daily rhythm in the migration of leukocytes to peripheral tissues 6 .In vertebrates, melatonin is known to be produced in a rhythmic manner by the pineal gland and retina, constitutively by the gastrointestinal tract and on demand by some immunocompetent cells 15,16 . Activated monocytes/macrophages/microglia and T lymphocytes expressed the enzymes arylalkylamine-N-acetyltransferase (AA-NAT), its active phosphorylated form (P-AA-NAT) and acetylserotonin-O-methyltransferase (ASMT) and melatonin 17-21 . In the spleen and in the bone marrow (BM), some works have shown the expression and activity of the melatonergic enzymes 22-24 , however, whether the immune cells of these organs also present www.nature.com/scientificreports www.nature.com/scientificreports/ circadian variations of the melaton...
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