title: Adenosine triphosphate inhibits melatonin synthesis in the rat pineal gland.
abstract: 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.
authors.affiliation: Laboratory of Chronopharmacology, Biosciences Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Luis Henrique
authors.identifier: http://orcid.org/0000-0002-3406-9351
authors.initials: LH
authors.lastname: Souza-Teodoro
authors.affiliation: Laboratory of Chronopharmacology, Biosciences Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Letícia
authors.initials: L
authors.lastname: Dargenio-Garcia
authors.affiliation: Laboratory of Chronopharmacology, Biosciences Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Camila Lopes
authors.initials: CL
authors.lastname: Petrilli-Lapa
authors.affiliation: Laboratory of Chronopharmacology, Biosciences Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Ewerton da Silva
authors.initials: Eda S
authors.lastname: Souza
authors.affiliation: Laboratory of Chronopharmacology, Biosciences Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Pedro A C M
authors.initials: PA
authors.lastname: Fernandes
authors.affiliation: Laboratory of Chronopharmacology, Biosciences Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Regina P
authors.initials: RP
authors.lastname: Markus
authors.affiliation: Laboratory of Chronopharmacology, Biosciences Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Zulma S
authors.initials: ZS
authors.lastname: Ferreira
mesh_terms: D000121:Acetylserotonin O-Methyltransferase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D005260:Female; D008297:Male; D008550:Melatonin / Q000096:biosynthesis*; D016328:NF-kappa B / Q000378:metabolism; D010870:Pineal Gland / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D058472:Receptors, Purinergic P2Y1 / Q000378:metabolism; D012701:Serotonin / Q000031:analogs & derivatives / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D058472:Receptors, Purinergic P2Y1; D012701:Serotonin; D000255:Adenosine Triphosphate; D000121:Acetylserotonin O-Methyltransferase; D010738:Type C Phospholipases; D008550:Melatonin; C006389:N-acetylserotonin
keywords: P2Y1 receptors; acetylserotonin O-methyltransferase; pinealocytes; purinergic signaling