The Thyrotropin-Releasing Hormone-Degrading Ectoenzyme, a Therapeutic Target?
Por:
Charli, Jean-Louis, Rodriguez-Rodriguez, Adair, Hernandez-Ortega, Karina, Cote-Velez, Antonieta, URIBE, ROSA MARIA, Jaimes-Hoy, Lorraine, Joseph-Bravo, Patricia
Publicada:
8 may 2020
Resumen:
Thyrotropin releasing hormone (TRH: Glp-His-Pro-NH2) 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-NH2 and Glp-Tyr-Pro-NH2, 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 beta 2-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.
Filiaciones:
Charli, Jean-Louis:
Univ Nacl Autonoma Mexico, Inst Biotecnol, Dept Genet & Desarrollo Fisiol Mol, Cuernavaca, Morelos, Mexico
Rodriguez-Rodriguez, Adair:
Univ Nacl Autonoma Mexico, Inst Biotecnol, Dept Genet & Desarrollo Fisiol Mol, Cuernavaca, Morelos, Mexico
Hernandez-Ortega, Karina:
Univ Nacl Autonoma Mexico, Inst Biotecnol, Dept Genet & Desarrollo Fisiol Mol, Cuernavaca, Morelos, Mexico
Cote-Velez, Antonieta:
Univ Nacl Autonoma Mexico, Inst Biotecnol, Dept Genet & Desarrollo Fisiol Mol, Cuernavaca, Morelos, Mexico
URIBE, ROSA MARIA:
Univ Nacl Autonoma Mexico, Inst Biotecnol, Dept Genet & Desarrollo Fisiol Mol, Cuernavaca, Morelos, Mexico
Jaimes-Hoy, Lorraine:
Univ Nacl Autonoma Mexico, Inst Biotecnol, Dept Genet & Desarrollo Fisiol Mol, Cuernavaca, Morelos, Mexico
Joseph-Bravo, Patricia:
Univ Nacl Autonoma Mexico, Inst Biotecnol, Dept Genet & Desarrollo Fisiol Mol, Cuernavaca, Morelos, Mexico
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