title: Balance between cAMP and Ca(2+) signals regulates expression levels of pituitary adenylate cyclase-activating polypeptide gene in neurons.
abstract: Mice lacking the gene encoding pituitary adenylate cyclase-activating polypeptide (PACAP) or its specific receptor, PAC1, show abnormal behaviors related to schizophrenia. However, the regulation of PACAP expression in neurons remains unclear. Here, we report that Pacap mRNA levels are regulated transcriptionally and post-transcriptionally by cAMP and Ca(2+) signals in cultured rat cortical cells. Pacap mRNA levels decreased proportionately with the intensity of cAMP signaling, and this decrease was accelerated by N-methyl-D-aspartate (NMDA) receptor blockade, suggesting that cAMP signaling enhances the degradation of Pacap mRNA, whereas NMDA receptor-mediated signals inhibit its degradation. However, depolarization (which produced a robust increase in Ca(2+) signals) together with cAMP signaling resulted in a synergistic induction of Pacap mRNA through calcineurin and its substrate, cAMP-response element-binding protein (CREB)-regulated transcription coactivator 1. These results strongly support the concept that while cAMP signaling can accelerate the degradation of Pacap mRNA, it can also synergistically enhance Ca(2+) signaling-induced transcriptional activation of Pacap. Taken together, our findings suggest that a balance between Ca(2+) and cAMP signals regulates PACAP levels in neurons and that a perturbation of this balance may result in psychiatric disorders, such as schizophrenia.
authors.affiliation: Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Fukuchi
authors.affiliation: Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kuwana
authors.affiliation: Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Tabuchi
authors.affiliation: Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Tsuda
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000235:genetics* / Q000378:metabolism; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide / Q000096:biosynthesis / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C519510:Crtc1 protein, rat; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D012333:RNA, Messenger; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D014157:Transcription Factors; D000242:Cyclic AMP; D019703:Calcineurin