Tryptophan hydroxylase-2: An emerging therapeutic target for stress disorders

Abstract

Serotonin (5-HT) has been long recognized to modulate the stress response, and dysfunction of 5-HT has been implicated in numerous stress disorders. Accordingly, the 5-HT system has been targeted for the treatment of stress disorders. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT synthesis, and the recent identification of a second, neuron-specific TPH isoform (TPH2) opened up a new area of research. With a decade of extensive investigation, it is now recognized that: 1) TPH2 exhibits a highly flexible gene expression that is modulated by an increasing number of internal and external environmental factors including the biological clock, stressors, endogenous hormones, and antidepressant therapies; and 2) genetically determined TPH2 activity is linked to a growing body of stress-related neuronal correlates and behavioral traits. These findings reveal an active role of TPH2 in the stress response and provide new insights into the long recognized but not yet fully understood 5-HT-stress interaction. As a major modulator of 5-HT neurotransmission and the stress response, TPH2 is of both pathophysiological and pharmacological significance, and is emerging as a new therapeutic target for the treatment of stress disorders. Given that numerous antidepressant therapies influence TPH2 gene expression, TPH2 is already inadvertently targeted for the treatment of stress disorders. With increased understanding of the regulation of TPH2 activity we can now purposely utilize TPH2 as a target to develop new or optimize current therapies, which are expected to greatly improve the prevention and treatment of a wide variety of stress disorders.

Physical Weight Loading Induces Expression of Tryptophan Hydroxylase 2 in the Brain Stem

“…The 28 d voluntary exercise has been shown to induce tph2 in hippocampus, suggesting anti-depressant effects of brain serotonin [27]. Tph2 has been also suggested as a therapeutic target for stress disorders [28]. Yet, in this study, we did not observe a significant alteration of tph2 in the rostral subdivision along with FC and VMH.…”

Negative effects on newborn piglets caused by excess dietary tryptophan in the morning in sows

“…In addition to the above‐mentioned functions, a link between Trp metabolism and the circadian rhythm has been reported . During pregnancy, Trp derivatives, such as serotonin and melatonin, play important roles in circadian rhythms . Notably, either directly or indirectly via the melatonin rhythm, the optimal maternal circadian rhythm is important for the programming of the fetal circadian rhythm .…”

“…5 During pregnancy, Trp derivatives, such as serotonin and melatonin, play important roles in circadian rhythms. 6,7 Notably, either directly or indirectly via the melatonin rhythm, the optimal maternal circadian rhythm is important for the programming of the fetal circadian rhythm. 7 A disturbed maternal circadian rhythm, referred to as chronodisruption, may lead to psychological and behavioral problems in the newborn.…”

Perturbations of Neuron-Restrictive Silencing Factor Modulate Corticotropin-Releasing Hormone Gene Expression in the Human Cell Line BeWo

“…JX896971), expressing the N-terminal NRSF4 isoform had been previously cloned into the pcDNA3.1/ V5-His-TOPO ® vector (Invitrogen, USA, Cat. K480040) [30]. Due to the failure of obtaining the full-length coding region of NRSF by PCR amplification of cDNA samples derived from human tissues and cell lines [30], two PCR-amplified, overlapping fragments of NRSF -E 1a /E 2 /E 3 /E 4-partial (F1, amplified by primers E 1a F 2 [5′-ccagcacccaactttaccac-3′] and E 4 R 3 [5′-cacataactgcactgatcacattta-3′]) and E 2-partial /E 3 /E 4-full (F2, amplified by primers E 2 F 1 [5′-cagtgagcgagtatcactgga-3′] and E 4 R 2 [5′-caaactaagaactgaaaccttgttca-3′]), were first cloned into pcDNA3.1, respectively.…”

“…K480040) [30]. Due to the failure of obtaining the full-length coding region of NRSF by PCR amplification of cDNA samples derived from human tissues and cell lines [30], two PCR-amplified, overlapping fragments of NRSF -E 1a /E 2 /E 3 /E 4-partial (F1, amplified by primers E 1a F 2 [5′-ccagcacccaactttaccac-3′] and E 4 R 3 [5′-cacataactgcactgatcacattta-3′]) and E 2-partial /E 3 /E 4-full (F2, amplified by primers E 2 F 1 [5′-cagtgagcgagtatcactgga-3′] and E 4 R 2 [5′-caaactaagaactgaaaccttgttca-3′]), were first cloned into pcDNA3.1, respectively. The two constructs (F1 and F2) were then subject to double digestion with SwaI and NotI, which uniquely cuts the sequence at proximal E 4 and 3′-end of the TA cloning site, respectively.…”