The Thyrotropin-Releasing Hormone-Degrading Ectoenzyme, a Therapeutic Target?

Abstract

Thyrotropin releasing hormone (TRH: Glp-His-Pro-NH 2) is a peptide mainly produced by brain neurons. In mammals, hypophysiotropic TRH neurons of the paraventricular nucleus of the hypothalamus integrate metabolic information and drive the secretion of thyrotropin from the anterior pituitary, and thus the activity of the thyroid axis. Other hypothalamic or extrahypothalamic TRH neurons have less understood functions although pharmacological studies have shown that TRH has multiple central effects, such as promoting arousal, anorexia and anxiolysis, as well as controlling gastric, cardiac and respiratory autonomic functions. Two G-protein-coupled TRH receptors (TRH-R1 and TRH-R2) transduce TRH effects in some mammals although humans lack TRH-R2. TRH effects are of short duration, in part because the peptide is hydrolyzed in blood and extracellular space by a M1 family metallopeptidase, the TRH-degrading ectoenzyme (TRH-DE), also called pyroglutamyl peptidase II. TRH-DE is enriched in various brain regions but is also expressed in peripheral tissues including the anterior pituitary and the liver, which secretes a soluble form into blood. Among the M1 metallopeptidases, TRH-DE is the only member with a very narrow specificity; its best characterized biological substrate is TRH, making it a target for the specific manipulation of TRH activity. Two other substrates of TRH-DE, Glp-Phe-Pro-NH 2 and Glp-Tyr-Pro-NH 2, are also present in many tissues. Analogs of TRH resistant to hydrolysis by TRH-DE have prolonged central efficiency. Structure-activity studies allowed the identification of residues critical for activity and specificity. Research with specific inhibitors has confirmed that TRH-DE controls TRH actions. TRH-DE expression by b2-tanycytes of the median eminence of the hypothalamus allows the control of TRH flux into the hypothalamus-pituitary portal vessels and may regulate serum thyrotropin secretion. In this review we describe the critical evidences that suggest that modification of TRH-DE activity in tanycytes, and/or in other brain regions, may generate beneficial consequences in some central and metabolic disorders and identify potential drawbacks and missing information needed to test these hypotheses.

Sex-specific multi-level 3D genome dynamics in the mouse brain

“…In particular, Adcyap1 encodes pituitary adenylate cyclase activating polypeptide (PACAP), a critical sex-specific and oestrogen-dependent regulator of the stress response 58 which has been associated with sex-specific anxiety-related behaviour in rodents 39 and female-specific risk for PTSD in humans 40 . Moreover, we observed differential E–P interactions and changes in the expression of genes such as Pou3f2 59 , Trhde 60 , and Gfra2 61 , which are associated with psychiatric disorders in humans and anxiety and depression-related behaviours in mice. While our E–P results were obtained by examining significant interactions in Hi-C data, future work using methods that are specific for E–P interactions, such as HiChIP 62 for H3K4me1 or H3K27ac, may identify additional sex specific- or sex hormone-driven E–P interactions critical for gene regulation and neuronal function.…”

Sex-specific multi-level 3D genome dynamics in the mouse brain

“…In particular, Adcyap1 encodes pituitary adenylate cyclase activating polypeptide (PACAP), a critical sex-specific and estrogen-dependent regulator of the stress response ( 48 ) which has been associated with sex-specific anxiety-related behavior in rodents ( 35 ) and female-specific risk for PTSD in humans ( 36 ). Moreover, we observed differential E-P interactions and changes in the expression of genes such as Pou3f2 ( 49 ), Trhde ( 50 ), and Gfra2 ( 51 ), which are associated with psychiatric disorders in humans and anxiety and depression-related behaviors in mice. Therefore, considering the importance of 3D genome organization for gene regulation and cellular function, our results provide a new molecular mechanism for sex specific- and sex hormone-driven neuronal gene regulation, neural plasticity, and behavioral phenotypes.…”

Rifaximin modulates TRH and TRH-like peptide expression throughout the brain and peripheral tissues of male rats

“…The TRH-degrading serum enzyme is a product of liver [ 48 ]. It rapidly metabolizes TRH and most TRH-like peptides in the circulation except Glu-TRH [ 49 ]. Rifaximin is used for the prevention of recurrent overt hepatic encephalopathy [ 50 ].…”