Tryptophan hydroxylase 2 (TPH2) in a neuronal cell line: modulation by cell differentiation and NRSF/rest activity

Authors

  • Maria Teresa Gentile,

    1. Department of Environmental, Biological and Pharmaceutical Sciences and Technology, Second University of Naples, Caserta, Italy
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    • These two authors equally contributed to the work.
  • Yukino Nawa,

    1. Institute of Radioisotope Research, Department of Molecular and Behavioral Neuroscience, St. Marianna University Graduate School of Medicine, Kawasaki, Japan
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    • These two authors equally contributed to the work.
  • Gianluigi Lunardi,

    1. Oncology Department, San Cuore Don Calabria Hospital, Negrar (VR), Italy
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  • Tullio Florio,

    1. Section of Pharmacology, Department of Internal Medicine and Center of Excellence for Biomedical Research (CEBR), University of Genova, Italy
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  • Hiroaki Matsui,

    1. Institute of Radioisotope Research, Department of Molecular and Behavioral Neuroscience, St. Marianna University Graduate School of Medicine, Kawasaki, Japan
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  • Luca Colucci-D'Amato

    Corresponding author
    • Department of Environmental, Biological and Pharmaceutical Sciences and Technology, Second University of Naples, Caserta, Italy
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Address correspondence and reprint requests to Luca Colucci-D'Amato, Department of Environmental, Biological and Pharmaceutical Sciences and Technology, Second University of Naples, Via Vivaldi 43, 81100 Caserta, Italy. E-mail: luca.colucci@unina2.it

Abstract

Serotonin (5-HT) is a neurotransmitter involved in many aspects of the neuronal function. The synthesis of 5-HT is initiated by the hydroxylation of tryptophan, catalyzed by tryptophan hydroxylase (TPH). Two isoforms of TPH (TPH1 and TPH2) have been identified, with TPH2 almost exclusively expressed in the brain. Following TPH2 discovery, it was reported that polymorphisms of both gene and non-coding regions are associated with a spectrum of psychiatric disorders. Thus, insights into the mechanisms that specifically regulate TPH2 expression and its modulation by exogenous stimuli may represent a new therapeutic approach to modify serotonergic neurotransmission. To this aim, a CNS-originated cell line expressing TPH2 endogenously represents a valid model system. In this study, we report that TPH2 transcript and protein are modulated by neuronal differentiation in the cell line A1 mes-c-myc (A1). Moreover, we show luciferase activity driven by the human TPH2 promoter region and demonstrate that upon mutation of the NRSF/REST responsive element, the promoter activity strongly increases with cell differentiation. Our data suggest that A1 cells could represent a model system, allowing an insight into the mechanisms of regulation of TPH2 and to identify novel therapeutic targets in the development of drugs for the management of psychiatric disorders.

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