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.
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Abbreviations
- AZ:
-
Antizyme
- AZIN:
-
Antizyme inhibitor
- BMMCs:
-
Bone marrow derived mast cells
- HDC:
-
Histidine decarboxylase
- ODC:
-
Ornithine decarboxylase
- TPH1:
-
Tryptophan hydroxylase-1
- MITF:
-
Microphtalmia-associated transcription factor
- mMCP-6:
-
Mouse mast cell protease-6
- mMC-CPA:
-
Mouse mast cell carboxypeptidase A
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Acknowledgments
This work was funded by Grants PAIDI2010-06585 (Junta de Andalucía, Spain), SAF2011-26518 (Ministerio de Economía y Competitividad, Spain) to FSJ and SAF2011-29051 to RP (Ministerio de Economía y Competitividad, co-financed with FEDER funds). CIBER-ER is an initiative of Instituto de Salud Carlos III (Spain). We are grateful to Dr. Miguel Ángel Medina (University of Málaga, Spain) for helpful discussions.
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The authors declare that they have no conflict of interest.
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Acosta-Andrade, C., Lambertos, A., Urdiales, J.L. et al. A novel role for antizyme inhibitor 2 as a regulator of serotonin and histamine biosynthesis and content in mouse mast cells. Amino Acids 48, 2411–2421 (2016). https://doi.org/10.1007/s00726-016-2230-3
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DOI: https://doi.org/10.1007/s00726-016-2230-3