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Query: HUMANGGP:012528 (thyrotropin-releasing hormone)
3,440 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Preferable conformations of thyrotropin-releasing hormone (TRH, Glp-His-Pro-NH2) and its analogues Glp-Glu(R)-Pro-NH2 (R = NHCH(CH3)CH2Ar), Glp-Gln-Abu-NH2, Dho-Gln-Abu-NH2 in DMSO solution are determined using two-dimensional 1H NMR spectroscopy (delta-J-correlated, COSY and NOESY). Torsion angles psi i and chi i for every amino acid were calculated on the basis of the spin-spin coupling constants 3JNH-C alpha H and 3JC alpha H-C beta H values. The NOESY data were used for selecting the peptide conformations realized in solution. Distances between protons interacting by the dipole mechanism (d-contacts) were calculated using NOE values. These experiments allow one to estimate the torsion angles psi (between C alpha H-CO). TRH has an intramolecular H-bond between NH2-protons and His carbonyl with the torsion angles omega 3 = 180 degrees and psi 3 = 0 degrees. It is formation of this H-bond that apparently promotes the domination of the trans configuration of the His-Pro peptide bond. An intramolecular NH2-C alpha CO (Glp) H-bonding is revealed in other investigated compounds. It is known that a similar conformation of the TRH is realized in the course of its interaction with receptor.
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PMID:[Conformational analysis of biologically active thyroliberin analogs by two-dimensional NMR spectroscopy]. 160 1

[3H](3-Me-His2) thyrotropin-releasing hormone ([3H]MeTRH) bound to TRH receptors in rodent, rabbit and dog brain and spinal cord (SC), and in rat, sheep, bovine and dog anterior pituitary (PIT) glands, with high affinity (dissociation constants, KdS = 5-9 nM; n = 3-4) but to different densities of these sites (Bmax range 6-145 fmol/mg protein) (rabbit SC greater than sheep PIT much greater than G.pig brain greater than dog brain greater than rat brain greater than bovine and dog PIT). Various TRH analogs competitively inhibited [3H]MeTRH binding in these tissues with a similar rank order of potency: MeTRH greater than TRH greater than CG3703 greater than or equal to RX77368 greater than or equal to MK-771 greater than TRH Glycinamide greater than Glu1-TRH much greater than CG3509 greater than or equal to NVal2-TRH much much greater than TRH free acid much much greater than and cyclo-His-Pro, indicating a pharmacological similarity of CNS and pituitary TRH receptors. While most TRH analogs displaced [3H]MeTRH binding with a similar potency in the different species, TRH exhibited a 2-fold lower affinity in the rat and G.pig brain than in other tissues of other species. Similarly, CG3703 was 2.4-4.5 times more active in the rabbit brain than in the rodent and dog brain, and also more potent in the rabbit brain as compared to the sheep PIT.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Analogs of thyrotropin-releasing hormone (TRH): receptor affinities in brains, spinal cords, and pituitaries of different species. 165 1

Indirect immunofluorescence histochemistry was used to investigate the distribution and extent of co-localization of chemical messengers in magnocellular neurons of the supraoptic and paraventricular nuclei. In order to increase the number of neurons immunoreactive to the antisera used, experimental manipulations were employed. The homozygous Brattleboro (diabetes insipidus) rat was also investigated. In untreated rats, only vasopressin- and oxytocin-like immunoreactivities could be observed. Colchicine treatment alone resulted in appearance of galanin-, dynorphin-, cholecystokinin-, [Leu]enkephalin- and thyrotropin-releasing hormone-positive cells. In hypophysectomized rats, all these markers, except tyrosine hydroxylase, showed substantial further increases. In addition, peptide histidine-isoleucine-immunoreactive cell bodies could now be seen. After salt-loading alone, tyrosine hydroxylase-like immunoreactivity was markedly increased, whereas vasopressin- and oxytocin-like immunoreactivity were very weak or undetectable. When salt-loaded rats received colchicine, corticotropin-releasing factor- and peptide histidine-isoleucine-like immunoreactivity in addition increased, whereas galanin- and dynorphin-like immunoreactivity markedly decreased. The Brattleboro rats resembled untreated rats, except their lack of vasopressin-like immunoreactivity, the marked increase in tyrosine hydroxylase-like immunoreactivity, and smaller increase in galanin- and dynorphin-like immunoreactivity. Addition of colchicine to Brattleboro rats resulted in some distinct further changes in that dynorphin-like immunoreactivity decreased in some neurons and that [Leu]enkephalin-, corticotropin-releasing factor- and peptide histidine-isoleucine-like immunoreactivity increased substantially. Several similarities could be observed between the salt-loaded and Brattleboro rats, with or without colchicine. However, a marked difference in immunoreactive [Leu]enkephalin levels was observed with no difference in dynorphin-like immunoreactivity, and opposite changes in galanin-like immunoreactivity. The results confirm the traditional view that hypothalamic magnocellular neurons in the supraoptic and paraventricular nuclei contain two separate cell populations, characterized by vasopressin and oxytocin, respectively, and that they contain additional messenger molecules in specific patterns. Vasopressin-containing neurons primarily express tyrosine hydroxylase, galanin, dynorphin, [Leu]enkephalin and peptide histidine-isoleucine, and to a minor extent cholecystokinin and thyrotropin-releasing hormone. Oxytocin-containing neurons mainly have cholecystokinin and corticotropin-releasing factor, and to a minor extent galanin, dynorphin, [Leu]enkephalin and thyrotropin-releasing hormone. Furthermore, our results detail individual co-existence situations among these putative messenger molecules. Thus, magnocellular neurons respond in a differential way to various stimuli and they store multiple bioactive substances in specific combinations.
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PMID:Localization of chemical messengers in magnocellular neurons of the hypothalamic supraoptic and paraventricular nuclei: an immunohistochemical study using experimental manipulations. 170 Oct 38

Thyrotropin-releasing hormone prohormone contains five copies of the thyrotropin-releasing hormone progenitor sequence Gln-His-Pro-Gly, each flanked by pairs of basic amino acids and separated by intervening sequences (connecting peptides). Using a perifusion system for rat hypothalamic slices, we have studied the ionic mechanisms underlying the release of two connecting peptides originating from the thyrotropin-releasing hormone precursor: prepro-thyrotropin-releasing hormone-(160-169) (Ps4) and prepro-thyrotropin-releasing hormone-(178-199) (Ps5). Quantification of these two peptides in the effluent fluid was performed using sensitive and highly specific radioimmunoassay procedures. Reverse phase high performance liquid chromatography analysis of the effluent perifusate showed that released peptides co-eluted with synthetic Ps4 and Ps5. The secretion of Ps4 and Ps5 was stimulated by depolarizing agents such as (i) high potassium concentrations, (ii) ouabain, an Na+/K(+)-ATPase inhibitor, and (iii) veratridine, a stimulator of voltage-operated Na+ channels. The response to potassium (70 mM) was not affected by the specific Na+ channel blocker tetrodotoxin. The K+ channel blocker tetraethylammonium did not modify K(+)-evoked release of Ps4 and Ps5. These data suggest that voltage-operated Na+ channels are not involved in the stimulatory effect of high K+ on the release of Ps4 and Ps5. The lack of effect of picrotoxin, a Cl- channel blocker, on the secretion of the connecting peptides indicates that chloride ions play a minor role in the release process. In contrast, deprivation of Ca2+ in the perifusion medium suppressed K(+)-evoked release of the two peptides, indicating that voltage-operated Ca2+ channels are implicated in the release process. Taken together, the present results show that non-thyrotropin-releasing hormone peptides originating from the thyrotropin-releasing hormone precursor are secreted by mediobasal hypothalamic fragments. The release of these peptides is stimulated by depolarization through a calcium-dependent process. These data indicate that Ps4 and Ps5 may be released at the level of the median eminence into the portal circulation, suggesting that these peptides may play a role in the control of anterior pituitary cells.
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PMID:Release of pro-thyrotropin-releasing hormone connecting peptides PS4 and PS5 from perifused rat hypothalamic slices. 172 91

Histidyl-proline diketopiperazine [cyclo(His-Pro)] has recently been shown to inhibit prolactin (PRL) secretion in vitro and in vivo. This peptide is well known as a metabolite of thyrotropin-releasing hormone (TRH), which is one of the endogenous secretagogues of PRL. In this study, we investigated the effect of cyclo (His-Pro) on the cytosolic Ca2+ concentration [[Ca2+]i) in cultured lactotrophs by using a lactotroph-enriched fraction separated from female rat pituicytes by centrifugal elutriation. TRH (10 nM) induced a rapid rise in [Ca2+]i in the lactotrophs, followed by a plateau phase of prolonged increase in [Ca2+]i. In contrast, the addition of 100 microM of cyclo (His-Pro) caused no changes in the basal level or the TRH-induced plateau response of [Ca2+]i. Although pretreatment with cyclo (His-Pro) tended to decrease the biphasic increase in [Ca2+]i induced by TRH, the inhibitory effect was not statistically significant. These results demonstrated that cyclo (His-Pro) has no effect on [Ca2+]i in lactotrophs, and does not affect the TRH-induced increase in [Ca2+]i, indicating that the inhibition of PRL secretion by cyclo (His-Pro) may be primarily mediated by other intracellular messengers such as cyclic nucleotides and secondarily involved in other inhibitory systems including that of dopamine.
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PMID:Lack of effect of histidyl-proline diketopiperazine on basal level and TRH-induced response of cytosolic calcium concentration in rat lactotrophs. 179 30

A thyrotropin-releasing hormone (TRH) precursor peptide, pGlu-His-Pro-Gly (TRH-Gly) and related peptides were measured in human cerebrospinal fluid (CSF) with a TRH-Gly radiommunoassay and the levels of immunoreactivity (IR) were found to be 136- to 352-fold higher than the corresponding levels of TRH-IR. TRH-IR levels in CSF are elevated during the active phase of multiple sclerosis (MS). We have used this TRH-Gly RIA to determine whether this TRH precursor peptide is also elevated in CSF from MS and Alzheimer's (ALZ) disease patients in comparison with the corresponding levels in non-central nervous system disease (control) patients. A highly significant increase in TRH-Gly-IR was observed in MS and ALZ CSF samples compared to control CSF. Cation exchange and exclusion chromatography of extracts of mixtures of CSF and synthetic TRH-Gly revealed two peaks of TRH-Gly-IR. One cochromatographed with synthetic TRH-Gly and the other was attributable to the formation of a complex between TRH-Gly and a binding substance originating in CSF. Corresponding studies with extracts of mixtures of CSF and synthetic TRH revealed no evidence for TRH binding with any component of CSF. Reverse-phase high-pressure liquid chromatography of pooled extracts of normal CSF revealed that about a third of the total TRH-Gly-IR coeluted with synthetic TRH-Gly. The half-time for in vitro metabolism of synthetic TRH-Gly in fresh CSF was 5 times longer than for synthetic TRH at 37 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:High levels of thyrotropin-releasing hormone precursor peptide immunoreactivity and binding substance occur in human cerebrospinal fluid. 190 38

Cyclo(His-Pro), or cHP, is a putative metabolite of thyrotropin-releasing hormone (TRH), and, like TRH, can inhibit food intake but requires higher doses. In attempts to improve the anorectic effects of cHP through modification of its structure, a number of its analogs were synthesized. These analogs or cHP itself were administered to rats either by intracerebroventricular (ICV) infusion or systemic injection, and their effects on food intake were measured. None of the synthetic analogs was more potent than cHP, although several analogs demonstrated comparable potencies to the parent compound. Interestingly, one cHP analog reversed the suppressive effect and stimulated feeding. This reversal, as well as the preservation of the anorectic effect by some but not all the analogs, suggests that the cHP effect on feeding does require specific structural features.
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PMID:The effects of the TRH metabolite cyclo(His-Pro) and its analogs on feeding. 190 10

The characteristics of thyrotropin-releasing hormone (TRH)-degrading enzyme in human serum were studied. Serum was incubated in 0.1 M phosphate buffer containing [proline-3H]TRH at 37 degrees C. A thin layer chromatography analysis of TRH degradation did not show any radioactive peak located in an acid TRH position, but apparent radioactive peaks corresponding to His-Pro and His-ProNH2 occurred in the presence of p-hydroxymercuriphenyl sulfonic acid, an inhibitor of proline dipeptidase. With ion exchange paper chromatography, the formation of 3H-labeled His-Pro and His-ProNH2 was estimated as an end point in the measurement of pyroglutamyl aminopeptidase (pGlu-peptidase) activity. An assay using p-hydroxymercuriphenyl sulfonic acid was developed to sensitively quantitate the pGlu-peptidase. Neither bacitracin nor p-chloromercuribenzoic acid increased the activity of pGlu-peptidase. The addition of EDTA, dithiothreitol, and o-phenanthroline significantly inhibited pGlu-peptidase activity, but neither iodoacetamide nor ethylmaleimide altered its activity. The pGlu-peptidase had a stereotypic specificity for the tripeptide, pGlu-His-ProNH2 of TRH, and its Km was 44.9 microM. The pGlu-peptidase activity was not changed by either hyper- or hypothyroidism. The present data indicate that a TRH-degrading enzyme in human serum possesses a nature identical to type II of pGlu-peptidase which is not altered by thyroid status.
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PMID:Thyrotropin-releasing hormone-degrading enzyme in human serum is classified as type II of pyroglutamyl aminopeptidase: influence of thyroid status. 197 97

The mechanism by which TRH-Gly (pGlu-His-Pro-Gly), a biosynthetic precursor of thyrotropin-releasing hormone (TRH, pGlu-His-Pro-NH2), stimulates pituitary thyrotropin (TSH) and prolactin release has been studied in urethane-anesthetized 2-month-old (250 g) male Sprague-Dawley rats and in vitro with GH3 cells, a rat anterior pituitary tumor cell line. We used specific radioimmunoassays to measure TRH-Gly and TRH levels in rat cortex, hypothalamus, medulla, eyes and whole blood as a function of the intracisternal (IC) dose of TRH and TRH-Gly administered 40 min prior to sacrifice. IC injection of 1.0 mg of TRH-Gly led to a significant (p less than 0.005) increase in the TRH levels in hypothalamus, medulla and blood. The relative potency of IC and intracardiac (IK) TRH and TRH-Gly release of rat TSH was compared by radioimmunoassay and further refined using estimates based on in vivo kinetics of TRH-Gly alpha-amidation. The binding of TRH-Gly to the plasma membrane receptors for TRH on GH3 cells was also investigated. In regard to TSH release, TRH-Gly given IC had only 0.042% of the potency of TRH given IC and was consistent with its rate of IC alpha-amidation. IK TRH-Gly had 0.16% of the potency of IK TRH of TSH release and was also consistent with its rate of intravascular conversion to TRH. The mean peak TSH response occurred at 20 min after IC TRH-Gly or IC TRH injection but the post-peak decline was slower for IC TRH-Gly.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Release of thyrotropin and prolactin by a thyrotropin-releasing hormone (TRH) precursor, TRH-Gly: conversion to TRH is sufficient for in vivo effects. 212 12

The effects of microinjection of the stable thyrotropin-releasing hormone (TRH) analog, RX 77368, [pGlu-His-(3,3'-dimethyl)-Pro-NH2] into the raphe pallidus on gastric acid secretion were studied in urethane-anesthetized rats with gastric fistula. RX 77368 microinjected into the raphe pallidus at doses of 0.07, 0.7 and 7.7 pmol induced a dose-dependent net stimulation of gastric acid secretion (7 +/- 4, 50 +/- 7 and 61 +/- 12 mumol/h respectively). The peak acid response was reached within 30 min and returned to basal level 90 min post-injection. The stimulatory effect was abolished by bilateral cervical vagotomy and pirenzepine pretreatment (1 mg/kg, i.v.). RX 77368 (7.7 pmol) microinjected into the inferior olive or pyramidal tract induced smaller or no gastric acid secretory response. These results demonstrate that chemical stimulation of the raphe pallidus increases gastric acid secretion through vagal pathways and peripheral muscarinic receptors. These data suggest that the nucleus raphe pallidus may be involved in vagal modulation of gastric acid secretion in the rat.
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PMID:Microinjection of TRH analogs into the raphe pallidus stimulates gastric acid secretion in the rat. 212 72

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