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Definition
Thyrotropin-releasing hormone (TRH), a neurohormone, is the simplest of the hypothalamic neuro- hormones. It consists of three amino acids in the sequence glutamic acid–histidine–proline. The structural simplicity of TRH is deceiving because this hormone actually has many functions. It stimulates the synthesis and secretion of thyrotropin by the anterior pituitary 1.

Related Peptides
The discovery of TRH led quickly to the discovery of other small peptides that regulate the secretion by the anterior pituitary of its tropic hormones. Such regulation is usually accomplished by increasing or decreasing stimulation. However, growth hormone appears mainly to be regulated by increasing or decreasing inhibition, though a growth-hormone-releasing factor has been identified. The peptide substances of which TRH was the first to be identified are often grouped as hypothalamic hypophysiotropic hormones 1.

Discovery
In 1969, a group led by Guillemin and another by Schally, having worked competitively for many years, announced that the hypothalamic substance that causes the anterior pituitary gland to release thyrotropin (thyroid-stimulating hormone, TSH) is L-pyroglutamyL-L-histidyl-L-proline- amide (L-pGlu-L-His-L-ProNH2). This tripeptide is now called thyrotropin-releasing hormone (TRH) 1.

Structural Characteristics
A post-translational enzymatic mode of TRH synthesis in amphibians was confirmed using molecular techniques. It was determined that frog DNA contained a segment of 478 nucleotides that coded for the amino-terminal region of pro-TRH, a 123-amino-acid precursor containing three copies of the progenitor sequence of TRH (Gln-His-Pro-Gly) flanked by paired dibasic residues and a fourth incomplete copy lacking the C-terminal glycine. A mammalian pro-TRH molecule was later identified in rat hypothalamus as a 255-amino-acid protein containing five copies of the amino acid sequence of the TRH progenitor. Human pro-TRH contains six copies. The biosynthesis of TRH is essentially a five-step process, beginning with transcription of DNA of the TRH gene to TRH mRNA within the cell nucleus. Transcription is followed by translation of the TRH mRNA to the pro-TRH peptide on the ribosome. The post-translational processing of TRH begins with excision of the progenitor peptides by the action of carboxy peptidases. This is followed by amidation of proline by peptidyl glycine alpha-amidating monoxygenase, the amide moiety being donated by the C-terminal glycine. Finally, cyclization of the N-terminal glutamine by glutaminyl cyclase is accomplished. Post-translational processing of TRH appears to be restricted to the neuronal perikarya because of lack of TRH progenitor immunoreactivity in axons or terminals of the median eminence or spinal cord. The post-translational processing of pro-TRH also gives rise to a number of other peptides that may have behavioral or physiological activity 1.

 

Mode of Action
Receptors for TRH are found on thyrotroph and mammotroph cells of the anterior pituitary and on neurons throughout the CNS. The structural and functional properties of both pituitary and central TRH receptors have been characterized in detail and shown to be similar in structure, binding characteristics, and mechanisms of signal transduction. TRH receptors belong to a class of G-protein-coupled receptors with seven membrane-spanning domains and an extracellular N-terminal region containing N-glycosylation sites. The basic cellular mechanisms of TRH actions on TSH and PRL secretion have been investigated using cultured pituitary tumor cells. The biphasic secretion of these two hormones has been shown to involve G-protein-coupled stimulation of inositol phospholipid turnover. The initial phase of hormone secretion is thought to result from inositol trisphosphate-mediated release of Ca2+ from intracellular stores; the second and more sustained phase results from influx of extracellular Ca2+ via voltage-sensitive channels activated by protein kinase C, which is induced by 1,2-DG. Stimulation of TRH receptors on thyrotroph tumor cells also induces the release of arachidonic acid metabolites that may act as additional intracellular messengers. In addition to stimulating TSH and PRL release, TRH regulates the transcription of PRL and the post-translational glycosylation of TSH 1.

Certain low affinity TRH analogs such as MeTRH, TRH-Gly (pGlu-His-Pro-GlyOH) and Phe2-TRH (pGlu-Phe-ProNH2), NP654 (pGlu-His(1-isopropyl)-ProNH2), 3R-Desaza-TRH ((1R)-(3-oxocyclopentyl)-His-ProNH2), and S-Desaza-TRH ((1S)-(3-oxocyclopentyl)-His-ProNH2) are more efficacious agonists at TRH-R1 and TRH-R2 than the cognate ligand TRH 2.

Functions
Anterior Pituitary Function: The unequivocal endocrine function of TRH is to stimulate the synthesis and release of TSH from thyrotroph cells of the anterior pituitary gland. Thus, TRH, in concert with thyroid hormones and the inhibitory influences of dopamine and somatostatin from the hypothalamus, controls pituitary TSH synthesis and release. TRH stimulates prolactin (PRL) release, but evidence that it is a major physiologic PRL-releasing factor is either species-specific or controversial.

Central Actions:  The central actions of TRH are myriad, affecting brain chemistry, physiology, and behavior. As a neuromodulator of several different neurotransmitters, including most prominently dopamine, serotonin, acetylcholine, and the opiates, TRH affects the actions of many drugs that themselves affect these and other neuro-transmitters.

TRH has been shown to arouse hibernating animals, through a hippocampal mechanism, and to antagonize the sedation, motor impairment, and hypothermia produced by ethanol and other CNS depressants. TRH counteracts the hypothemia or poikilothermia produced by various drugs and several endogenous neuropeptides, including neurotensin, bombesin, and betaendorphin. Its effects alone on body temperature are variable: TRH produces hypothermia in some species, hyperthermia in others, and in some it has no effect. Similarly, TRH stimulates locomotor activity by activation of the mesolimbic dopamine system. The tripeptide also produces profound stimulation of the cardiovascular and respiratory systems and induces increases in gastrointestinal motility and the volume and acidity of gastric secretion while often suppressing the intake of both food and water. These gastrointestinal effects of TRH may play a role in the ulcerogenic actions of TRH.

In Neurological Disorders: As described above, shortly after its discovery as a hypothalamic hypophysiotropic hormone, TRH was found to be distributed in many extrahypothalamic sites in brain, in spinal cord, and in other organ systems. The neuroanatomical location and neurochemical actions of TRH suggested that it could be utilized as a therapeutic agent in neurological and psychiatric disorders 1.


References

1.     Book: Focus on Basic Neurobiology. Thyrotropin-Releasing Hormone by Mason GA, Garbutt JC, Prange, Jr AJ  (2000).

2.     Engel S, Neumann S, Kaur N, Monga V, Jain R, Northup JGershengorn MC (2006). Low Affinity Analogs of Thyrotropin-releasing Hormone Are Super-agonists. The Journal of Biological Chemistry, 281(19):13103-13109.

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