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Questions And Answer

• Discovery

  TRH was first isolated and characterized in 1969 by Roger Guillemin and Andrew Schally, who shared the Nobel Prize in Physiology or Medicine in 1977 “for their discoveries concerning the peptide hormone production of the brain.”The biosynthesis of TRH from a precursor molecule was first clarified in 1984 by isolation of a preproTRH cDNA from the skin of Xenopus laevis.  The structure of the TRH receptor (TRH-R) was first deduced from a cDNA isolated from the mouse pituitary in 1990.;

• Properties

  Mr 362. Soluble in water, methanol, and ethanol; partially insoluble in chloroform; completely insoluble in ether and pyridine. Stable in solution at <15°C for more than a year; partially (1%) degraded at 40°C for 6 months. Resistant to proteolytic enzymes. Inactivated by diazotized sulfanilic acid (Pauly reagent). Plasma half-life is 2–6min.;

• Gene, mRNA, and precursor

  TRH is synthesized from a precursor that contains multiple copies of the TRH progenitor sequence GlnHis-Pro-Gly, which is flanked by dibasic cleavage sites at its N- and C-termini. The number of progenitor sequences in a precursor is diversified: six in humans, five in rats, four in chicken, seven in frogs, and six to eight in fish. Human preproTRH gene, TRH, location 3q13.3–q21, consists of three exons.;

• Synthesis and release

  TRH secretion is regulated by norepinephrine, histamine, dopamine, and serotonin. Cold-induced secretion of TSH from the rat anterior pituitary involves α-adrenergic regulation of TRH secretion. TRH neurons in the PVN are negatively regulated by thyroid hormones through a feedback mechanism. Locally produced T3 is taken by these neurons to regulate transcription, posttranslational modification, and degradation of TRH.;

• Clinical implications

  The majority of thyroid disfunction is due to primary thyroid disease. On the other hand, central thyroid disfunction is related to a disorder of the pituitary (TSH), hypothalamus (TRH), or hypothalamic-pituitary portal circulation. Isolated central hypothyroidism was reported in a patient with inactivating mutations in the TRH-R gene.;

• Receptors

  TRH-R is a seven-transmembrane-domain GPCR. Two major types of TRH-Rs (type I receptor including TRH-R1 and TRH-R3, and type II receptor [TRH-R2]), have been identified in vertebrates . Three and four subtypes of TRH-Rs have been identified in Xenopus laevis and teleost species, respectively. TRH action is mediated via a membrane receptor mainly coupled to Gq/11 protein. TRH induces the mobilization of intracellular Ca2+ and the activation of PKC in target cells.;

• Biological functions

  The Trh knockout mice show normal development, but exhibit tertiary hypothyroidism and hyperglycemia due to diminished insulin secretion. The Trh knockout mice show defects in cerebellar long-term depression and a motor learning deficit.The Trhr1 knockout mice exhibit central hypothyroidism showing a decrease in serum T3, T4, and PRL levels but not in serum TSH levels. The Trhr1 knockout mice exhibit normal growth and development but displayed increased anxiety and depression levels. The Trhr2 knockout mice are euthyroid with normal serum TSH levels and exhibit normal development and growth. The mutant females exhibited moderately increased depression and reduced anxiety phenotypes.;

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