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

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. TPH2 is the rate-limiting enzyme for the synthesis of serotonin, expressed almost exclusively in the brain. We found, in a CNS-derived cell line (A1 cells) that endogenous TPH2 increases upon differentiation, and in undifferentiated cells upon knock down of REST/NRSF. A1 cells represent a model to study the regulation of TPH2 and to identify targets to modulate serotonin neurotransmission. © 2012 International Society for Neurochemistry