Transcriptional regulation of tryptophan hydroxylase-2

Abstract

Dysregulation of serotonergic neurotransmission is a contributing cause of numerous pathologies. In the brain, the enzyme catalyzing the rate-limiting step in serotonin biosynthesis and thus controlling serotonin levels is tryptophan hydroxylase-2 (TPH2). The objective of this project is to study the regulation of TPH2 transcription by characterizing its promoter region. Study of the 5' flanking region of the human TPH2 gene by means of reporter gene assays resulted in the finding of a core promoter and a repressing element between positions -179 and -88 relative to the transcription start site. In addition, the TPH2 promoter could be activated by Ca++ mobilization in a cell-line model of serotonergic neurons, but not in other cell lines. In agreement, Ca++ mobilization in this model also induced endogenous transcription of TPH2. This work is the first one to identify the promoter region of the TPH2 gene and to report its activity-dependent regulation of transcription.