title: A novel role for antizyme inhibitor 2 as a regulator of serotonin and histamine biosynthesis and content in mouse mast cells.
abstract: Antizymes and antizyme inhibitors are key regulatory proteins of polyamine levels by affecting ornithine decarboxylase and polyamine uptake. Our previous studies indicated a metabolic interplay among polyamines, histamine and serotonin in mast cells, and demonstrated that polyamines are present in mast cell secretory granules, being important for histamine storage and serotonin levels. Recently, the novel antizyme inhibitor-2 (AZIN2) was proposed as a local regulator of polyamine biosynthesis in association with mast cell serotonin-containing granules. To gain insight into the role of AZIN2 in the biosynthesis and storage of serotonin and histamine, we have generated bone marrow derived mast cells (BMMCs) from both wild-type and transgenic Azin2 hypomorphic mice, and have analyzed polyamines, serotonin and histamine contents, and some elements of their metabolisms. Azin2 hypomorphic BMMCs did not show major mast cell phenotypic alterations as judged by morphology and specific mast cell proteases. However, compared to wild-type controls, these cells showed reduced spermidine and spermine levels, and diminished growth rate. Serotonin levels were also reduced, whereas histamine levels tended to increase. Accordingly, tryptophan hydroxylase-1 (TPH1; the key enzyme for serotonin biosynthesis) mRNA expression and protein levels were reduced, whereas histidine decarboxylase (the enzyme responsible for histamine biosynthesis) enzymatic activity was increased. Furthermore, microphtalmia-associated transcription factor, an element involved in the regulation of Tph1 expression, was reduced. Taken together, our results show, for the first time, an element of polyamine metabolism -AZIN2-, so far described as exclusively devoted to the control of polyamine concentrations, involved in regulating the biosynthesis and content of other amines like serotonin and histamine.
authors.affiliation: Department of Molecular Biology and Biochemistry, CIBER de Enfermedades Raras (CIBER-ER), Instituto de Investigación Biomédica de Málaga (IBIMA), Faculty of Sciences, University of Málaga, Campus de Teatinos s/n, 29071, Málaga, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Acosta-Andrade
authors.affiliation: Department of Biochemistry and Molecular Biology B and Immunology, School of Medicine, University of Murcia, Murcia, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Lambertos
authors.affiliation: Department of Molecular Biology and Biochemistry, CIBER de Enfermedades Raras (CIBER-ER), Instituto de Investigación Biomédica de Málaga (IBIMA), Faculty of Sciences, University of Málaga, Campus de Teatinos s/n, 29071, Málaga, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Urdiales
authors.affiliation: Department of Molecular Biology and Biochemistry, CIBER de Enfermedades Raras (CIBER-ER), Instituto de Investigación Biomédica de Málaga (IBIMA), Faculty of Sciences, University of Málaga, Campus de Teatinos s/n, 29071, Málaga, Spain.
authors.forename: Francisca
authors.initials: F
authors.lastname: Sánchez-Jiménez
authors.affiliation: Department of Biochemistry and Molecular Biology B and Immunology, School of Medicine, University of Murcia, Murcia, Spain.|Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Peñafiel
authors.affiliation: Department of Molecular Biology and Biochemistry, CIBER de Enfermedades Raras (CIBER-ER), Instituto de Investigación Biomédica de Málaga (IBIMA), Faculty of Sciences, University of Málaga, Campus de Teatinos s/n, 29071, Málaga, Spain. ifajardo@uma.es.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Fajardo
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D006632:Histamine / Q000096:biosynthesis*; D008407:Mast Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D012701:Serotonin / Q000096:biosynthesis*; D014365:Tryptophan Hydroxylase / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C549629:antizyme inhibitor 2, mouse; D012701:Serotonin; D006632:Histamine; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase
keywords: Antizyme inhibitor-2; Histamine; Mast cells; Polyamines; Serotonin