Advances in tryptophan hydroxylase‐2 gene expression regulation: New insights into serotonin–stress interaction and clinical implications

Abstract

Serotonin (5-HT) modulates the stress response by interacting with the hormonal hypothalamic-pituitary-adrenal (HPA) axis and neuronal sympathetic nervous system (SNS). Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT biosynthesis, and the recent identification of a second, neuron-specific TPH isoform (TPH2) opened up a new area of research. While TPH2 genetic variance has been linked to numerous behavioral traits and disorders, findings on TPH2 gene expression have not only reinforced, but also provided new insights into, the long-recognized but not yet fully understood 5-HT-stress interaction. In this review, we summarize advances in TPH2 expression regulation and its relevance to the stress response and clinical implications. Particularly, based on findings on rhesus monkey TPH2 genetics and other relevant literature, we propose that: 1) upon activation of adrenal cortisol secretion, the cortisol surge induces TPH2 expression and de novo 5-HT synthesis; 2) the induced 5-HT in turn inhibits cortisol secretion by modulating the adrenal sensitivity to ACTH via the suprachiasmatic nuclei (SCN)-SNS-adrenal system, such that it contributes to the feedback inhibition of cortisol production; 3) basal TPH2 expression or 5-HT synthesis, as well as early-life experience, influence basal cortisol primarily via the hormonal HPA axis; and 4) 5′- and 3′-regulatory polymorphisms of TPH2 may differentially influence the stress response, presumably due to their differential roles in gene expression regulation. Our increasing knowledge of TPH2 expression regulation not only helps us better understand the 5-HT-stress interaction and the pathophysiology of neuropsychiatric disorders, but also provides new strategies for the treatment of stress-associated diseases.

Brain serotonin deficiency leads to social communication deficits in mice

“…A deficit in central serotonin (5-HT) is thought to be associated with deteriorated stress coping behaviour, affective disorders and exaggerated violence [1]. In rodents, genetically or pharmacologically induced 5-HT reduction in the central nervous system (CNS) is related to a loss of avoidance behaviour and increased aggression [2,3], and is suggested to cause the loss of sexual preference [4,5].…”

Tryptophan-Related Signaling Molecules: Targets and Functions

“…When Trp is taken alone or with a drug that enhances serotonergic effects, it may provoke side effects (Fernstrom 2012 ). In fact serotonin neurotransmission comprises multiple consecutive processes including synthesis, storage/release, signaling, reuptake, and metabolism, of which the fi rst step, synthesis, is a critical modulator of serotonin neurotransmission (Chen and Miller 2012 ). Serotonin is synthesized by a two-step enzymatic reaction.…”

“…Subsequently aromatic amino acid decarboxylase (AAADC ) catalyzes the second step of serotonin synthesis (Chen and Miller 2012 ).…”

Paracrine control of steroidogenesis by serotonin in adrenocortical neoplasms

“…In fact, 5-HT both triggers corticotropin-releasing hormone (CRH) release from hypothalamic neurons and stimulates corticotropin (ACTH) secretion from pituitary corticotrophs (Chen and Miller, 2012;Jørgensen et al, 2002). The serotonergic control of the corticotropic function seems to play an important role in the physiology of the HPA axis Jørgensen, 2007).…”

“…The serotonergic control of the corticotropic function seems to play an important role in the physiology of the HPA axis Jørgensen, 2007). In particular, several observations have shown that central serotonergic pathways are involved in the circadian periodicity of ACTH production and the activation of HPA in response to stress (Chen and Miller, 2012). The receptor types involved in the control of ACTH secretion by 5-HT may vary among mammalian species.…”