| Definition | | | | shown to be similar in structure, binding |
| Thyrotropin-releasing hormone (TRH), a | | | | characteristics, and mechanisms of signal transduction. |
| neurohormone, is the simplest of the hypothalamic | | | | TRH receptors belong to a class of G-protein-coupled |
| neuro- hormones. It consists of three amino acids in | | | | receptors with seven membrane-spanning domains |
| the sequence glutamic acid–histidine–proline. | | | | and an extracellular N-terminal region containing |
| The structural simplicity of TRH is deceiving because | | | | N-glycosylation sites. The basic cellular mechanisms of |
| this hormone actually has many functions. It | | | | TRH actions on TSH and PRL secretion have been |
| stimulates the synthesis and secretion of thyrotropin | | | | investigated using cultured pituitary tumor cells. The |
| by the anterior pituitary 1. | | | | biphasic secretion of these two hormones has been |
| Related Peptides | | | | shown to involve G-protein-coupled stimulation of |
| The discovery of TRH led quickly to the discovery of | | | | inositol phospholipid turnover. The initial phase of |
| other small peptides that regulate the secretion by | | | | hormone secretion is thought to result from inositol |
| the anterior pituitary of its tropic hormones. Such | | | | trisphosphate-mediated release of Ca2+ from |
| regulation is usually accomplished by increasing or | | | | intracellular stores; the second and more sustained |
| decreasing stimulation. However, growth hormone | | | | phase results from influx of extracellular Ca2+ via |
| appears mainly to be regulated by increasing or | | | | voltage-sensitive channels activated by protein kinase |
| decreasing inhibition, though a | | | | C, which is induced by 1,2-DG. Stimulation of TRH |
| growth-hormone-releasing factor has been identified. | | | | receptors on thyrotroph tumor cells also induces the |
| The peptide substances of which TRH was the first | | | | release of arachidonic acid metabolites that may act |
| to be identified are often grouped as hypothalamic | | | | as additional intracellular messengers. In addition to |
| hypophysiotropic hormones 1. | | | | stimulating TSH and PRL release, TRH regulates the |
| Discovery | | | | transcription of PRL and the post-translational |
| In 1969, a group led by Guillemin and another by | | | | glycosylation of TSH 1. |
| Schally, having worked competitively for many years, | | | | Certain low affinity TRH analogs such as MeTRH, |
| announced that the hypothalamic substance that | | | | TRH-Gly (pGlu-His-Pro-GlyOH) and Phe2-TRH |
| causes the anterior pituitary gland to release | | | | (pGlu-Phe-ProNH2), NP654 |
| thyrotropin (thyroid-stimulating hormone, TSH) is | | | | (pGlu-His(1-isopropyl)-ProNH2), 3R-Desaza-TRH |
| L-pyroglutamyL-L-histidyl-L-proline- amide | | | | ((1R)-(3-oxocyclopentyl)-His-ProNH2), and |
| (L-pGlu-L-His-L-ProNH2). This tripeptide is now called | | | | S-Desaza-TRH ((1S)-(3-oxocyclopentyl)-His-ProNH2) |
| thyrotropin-releasing hormone (TRH) 1. | | | | are more efficacious agonists at TRH-R1 and TRH-R2 |
| Structural Characteristics | | | | than the cognate ligand TRH 2. |
| A post-translational enzymatic mode of TRH | | | | Functions |
| synthesis in amphibians was confirmed using molecular | | | | Anterior Pituitary Function: The unequivocal endocrine |
| techniques. It was determined that frog DNA | | | | function of TRH is to stimulate the synthesis and |
| contained a segment of 478 nucleotides that coded | | | | release of TSH from thyrotroph cells of the anterior |
| for the amino-terminal region of pro-TRH, a | | | | pituitary gland. Thus, TRH, in concert with thyroid |
| 123-amino-acid precursor containing three copies of | | | | hormones and the inhibitory influences of dopamine |
| the progenitor sequence of TRH (Gln-His-Pro-Gly) | | | | and somatostatin from the hypothalamus, controls |
| flanked by paired dibasic residues and a fourth | | | | pituitary TSH synthesis and release. TRH stimulates |
| incomplete copy lacking the C-terminal glycine. A | | | | prolactin (PRL) release, but evidence that it is a major |
| mammalian pro-TRH molecule was later identified in | | | | physiologic PRL-releasing factor is either |
| rat hypothalamus as a 255-amino-acid protein | | | | species-specific or controversial. |
| containing five copies of the amino acid sequence of | | | | Central Actions: The central actions of TRH are |
| the TRH progenitor. Human pro-TRH contains six | | | | myriad, affecting brain chemistry, physiology, and |
| copies. The biosynthesis of TRH is essentially a | | | | behavior. As a neuromodulator of several different |
| five-step process, beginning with transcription of DNA | | | | neurotransmitters, including most prominently |
| of the TRH gene to TRH mRNA within the cell | | | | dopamine, serotonin, acetylcholine, and the opiates, |
| nucleus. Transcription is followed by translation of the | | | | TRH affects the actions of many drugs that |
| TRH mRNA to the pro-TRH peptide on the ribosome. | | | | themselves affect these and other |
| The post-translational processing of TRH begins with | | | | neuro-transmitters. |
| excision of the progenitor peptidesby the action of | | | | TRH has been shown to arouse hibernating animals, |
| carboxy peptidases. This is followed by amidation of | | | | through a hippocampal mechanism, and to antagonize |
| proline by peptidyl glycine alpha-amidating | | | | the sedation, motor impairment, and hypothermia |
| monoxygenase, the amide moiety being donated by | | | | produced by ethanol and other CNS depressants. |
| the C-terminal glycine. Finally, cyclization of the | | | | TRH counteracts the hypothemia or poikilothermia |
| N-terminal glutamine by glutaminyl cyclase is | | | | produced by various drugs and several endogenous |
| accomplished. Post-translational processing of TRH | | | | neuropeptides, including neurotensin, bombesin, and |
| appears to be restricted to the neuronal perikarya | | | | betaendorphin. Its effects alone on body |
| because of lack of TRH progenitor immunoreactivity | | | | temperature are variable: TRH produces hypothermia |
| in axons or terminals of the median eminence or | | | | in some species, hyperthermia in others, and in some |
| spinal cord. The post-translational processing of | | | | it has no effect. Similarly, TRH stimulates locomotor |
| pro-TRH also gives rise to a number of other | | | | activity by activation of the mesolimbic dopamine |
| peptides that may have behavioral or physiological | | | | system. The tripeptide also produces profound |
| activity 1. | | | | stimulation of the cardiovascular and respiratory |
| Mode of Action | | | | systems and induces increases in gastrointestinal |
| Receptors for TRH are found on thyrotroph and | | | | motility and the volume and acidity of gastric |
| mammotroph cells of the anterior pituitary and on | | | | secretion while often suppressing the intake of both |
| neurons throughout the CNS. The structural and | | | | food and water. These gastrointestinal effects of |
| functional properties of both pituitary and central | | | | TRH may play a role in the ulcerogenic actions of |
| TRH receptors have been characterized in detail and | | | | TRH. |