Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:012528 (thyrotropin-releasing hormone)
 3,440 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To test the hypothesis that pGlu of the thyrotropin-releasing hormone (TRH, pGlu-His-ProNH2) binds to Asn289 in the third extracellular loop (EL3) of its receptor through a hydrogen bonding interaction, we converted Asn289 to Asp (N289D mutant) and measured the potencies of TRH and Pro1TRH for the wild-type and mutant receptors. TRH was 100 times less potent for the N289D receptor than for the wild-type. In contrast, Pro1TRH, which has a protonated proline in place of the pGlu of TRH, was 10 times more potent for the N289D receptor than for the wild-type. A similar result was obtained when Asn289 was converted to Glu, while the potency of Pro1TRH did not change when Asn289 was converted to Ala, confirming that the increased potency of Pro1TRH for the N289D receptor was due to a charge interaction between Pro1TRH and the mutant receptor. These findings are inconsistent with a previous model indicating a direct interaction of the pGlu of TRH with Asn110 in the third transmembrane helix of the receptor (Perlman et al. (1994) J. Biol. Chem. 269, 23383-23386). When Asn110 was converted to Asp (N110D mutant), unlike the N289D receptor, the potency of Pro1TRH for the N110D receptor was decreased by > 10-fold rather than increased. Therefore, a direct interaction of Asn110 with the pGlu of TRH could not be supported by our experiments. We propose a new model in which the pGlu of TRH binds to Asn289 in EL3 and conclude that, unlike catecholamines which bind completely within the transmembrane domain of their receptors, this tripeptide binds, at least in part, to the extracellular domain of its receptor.
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PMID:Identification of Asn289 as a ligand binding site in the rat thyrotropin-releasing hormone (THR) receptor as determined by complementary modifications in the ligand and receptor: a new model for THR binding. 757 28

In this article, two mouse monoclonal antibodies (83-7B5-A1 and 83-6B6-A10) and three rabbit polyclonal antibodies (1118, 8572, and 8577) directed against thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH2) are described. The anti-TRH antibodies were raised by immunization with a TRH-bovine serum albumin conjugate obtained by coupling of the CO2H group of pGlu-His-Pro-OH to NH2 groups in the protein. The monoclonal antibodies were produced by hybridoma clones obtained by the fusion of SP2/0 myeloma cells with spleen cells of an immunized BALB/c mouse. Both monoclonal antibodies were of the IgG1 (kappa) subclass. Characterization of the anti-TRH antibodies showed that in general they are specific for the pGlu-His moiety. The cross-reactivities for the TRH-like peptides [Glu1]TRH, [Glu2]TRH, and [Phe2]TRH are low, while alterations at the Pro-NH2 moiety of TRH are recognized to varying extents. The specificities of these antibodies are markedly different from those previously obtained using TRH coupled through the histidine residue to protein as the immunogen.
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PMID:Production and characterization of monoclonal and polyclonal antibodies against thyrotropin-releasing hormone. 759 Jul 93

Pro-thyrotropin-releasing hormone (proTRH) is the precursor to thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH2), the hypothalamic releasing factor that stimulates synthesis and release of thyrotropin from the pituitary gland. Five copies of the TRH progenitor sequence (Gln-His-Pro-Gly) and seven cryptic peptides are formed following posttranslational proteolytic cleavage of the 26-kDa rat proTRH precursor. The endopeptidase(s) responsible for the physiological conversion of proTRH to the TRH progenitor form is currently unknown. We examined the in vitro processing of [3H]leucine-labeled or unlabeled proTRH by partially purified recombinant PC1. Recombinant PC1 processed the 26-kDa TRH precursor by initially cleaving the prohormone after the basic amino acid at either position 153 or 159. Based on the use of our well-established antibodies, we propose that the initial cleavage gave rise to the formation of a 15-kDa N-terminal peptide (preproTRH25-152 or pre-proTRH25-158) and a 10-kDa C-terminal peptide (pre-proTRH154-255 or preproTRH160-255). Some initial cleavage occurred after amino acid 108 to generate a 16.5-kDa C-terminal peptide. The 15-kDa N-terminal intermediate was further processed to a 6-kDa peptide (prepro-TRH25-76 or preproTRH25-82) and a 3.8-kDa peptide (preproTRH83-108), whereas the 10-kDa C-terminal intermediate was processed to a 5.4-kDa peptide (prepro-TRH206-255). The optimal pH for these cleavages was 5.5. ZnCl2, EDTA, EGTA, and the omission of Ca2+ inhibited the formation of pYE27 (preproTRH25-50), one of the proTRH N-terminal products, by 48, 82, 72, and 45%, respectively. This study provides evidence, for the first time, that recombinant PC 1 enzyme can process proTRH to its predicted peptide intermediates.
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PMID:Pro-thyrotropin-releasing hormone processing by recombinant PC1. 759 40

The effect of serotonin (5-HT) and thyrotropin-releasing hormone (TRH) analogue, p-Glu-His-[3,3'-dimethyl]-Pro-NH2 (RX-77368), injected into the dorsal vagal complex (DVC) on gastric acid secretion was assessed in urethan-anesthetized rats with gastric cannula. 5-HT (0.1, 0.2, 1, or 10 nmol into the DVC) enhanced the acid response to RX-77368 (25 pmol, DVC) by 54, 100, 147, and 144%, respectively, whereas 5-HT given alone had no effect. The 5-HT2 receptor agonists (1 nmol, DVC), ( +/- )-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride, 1-(alpha, alpha, alpha-trifluoro-m-tolyl)-piperazine hydrochloride, and alpha-methyl-5-HT increased the gastric acid response to coinjection of RX-77368 (25 pmol) by 153, 108, and 96%, respectively, whereas 8-hydroxy-2-(di-n-propylamino)tetralin (5-HT1A), 7-trifluoromethyl-4(4-methyl-1-piperazinyl)- pyrrolo[1,2-a]quinoxaline (5-HT1A/1B), and 3-(2-aminoethyl)-2-methyl-1-H-indol-5-ol hydrochloride hydrate (2-methyl-5-HT3) did not. The 5-HT2 receptor antagonist, 3-[2-(4-fluorobenzoyl)-1-piperdinyl]ethyl]-2,4(1H,3H)-quinazoli nedone tartrate (ketanserin; 20 nmol), injected intracisternally abolished the potentiating action of 5-HT injected into the DVC with RX-77368, whereas the 5-HT antagonists 8-[4-(4-fluorophenyl)-4-oxobutyl]-1-phenyl-1,3,8-triazaspiro[4,5]- decan-4-one (spiperone; 5-HT2/1A) and 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1- yl)methyl]-4H-carbazol-4-one hydrochloride dihydrate (ondansetron; 5-HT3) did not. Ketanserin (1 nmol/site bilaterally into the DVC) decreased the acid response to kainic acid injected into the raphe pallidus by 62%. These data suggest that 5-HT acting at 5-HT2 receptors in the DVC potentiates the gastric acid response to exogenous and endogenous TRH.
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PMID:Serotonin enhances gastric acid response to TRH analogue in dorsal vagal complex through 5-HT2 receptors in rats. 763 81

The efficacy of thyrotropin-releasing hormone (TRH) and its analogs to potentiate the spinal monosynaptic reflex was studied in isolated cords. The analogs examined were L-pyro-2-aminoadipyl-histidyl-thizolidine-4-carboxyamide (MK-771); pyroglutamyl-histidyl-prolineamide (TRH); pyroglutamyl-L-histidyl-3,3'-dimethyl-prolineamide (RX77368); (3-methyl-His2)TRH(methyl-TRH); gamma-buturolactone-gamma-carbonyl-histidyl-prolineamide citrate (DN-1417); pyroglutamyl-histidyl-proline (TRH-free acid); and histidyl-proline-diketopiperazine (cyclo(His-Pro)). The TRH analogs potentiated the monosynaptic reflex in a dose-dependent manner and the maximal potentiation occurred at about 1 microM. TRH-free acid potentiated the monosynaptic reflex but the maximal potentiation occurred at 100 times the TRH concentration. Cyclo(His-Pro) was totally ineffective. The concentration required to potentiate the monosynaptic reflex by 50% of the maximal response (EC50) was taken as an index for comparing various analogs in relation to TRH. The EC50 values of the analogs did not differ significantly from each other. However, the ratio of the mean value of an analog to that of TRH was of the following order: MK-771 (N- and C-terminally altered) > or = TRH > or = DN-1417 (N-terminal) > or = methyl-TRH > or = RX77368 (C-terminal) >>> TRH-free acid. Cyclo(His-Pro) was ineffective.
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PMID:Analogs of thyrotropin-releasing hormone in potentiating the spinal monosynaptic reflex in vitro. 770 44

A 16-year-old depressed adolescent, who had received sertraline treatment for the previous 18 months, developed insomnia, daytime somnolence and lack of energy. His thyroid function tests revealed low levels of total T4 with normal levels of free T4 and TSH, and a normal thyrotropin-releasing hormone (TRH) stimulation test. Discontinuing sertraline resulted in improved sleep and disappearance of daytime somnolence. Although daytime somnolence and low levels of total T4 can mimic hypothyroidism, in this case sertraline only displaced the bound-fraction of total T4 and was not associated with true hypothyroidism.
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PMID:Effects of long term treatment with sertraline (Zoloft) simulating hypothyroidism in an adolescent. 777 34

The membrane-bound enzyme which catalyzes the degradation of thyrotropin-releasing hormone (TRH; Glp-His-Pro-NH2) could be released from membranes of rat and pig brain by treatment with trypsin under very mild incubation conditions. The solubilized enzyme was purified 200,000-fold, with an overall yield of 20%, by conventional chromatographic methods. The enzyme preparation appeared to be electrophoretically homogenous since SDS/PAGE analysis revealed a single band with a molecular mass of 116,000 Da. By gel-filtration chromatography, a molecular mass of 230,000 Da was estimated, suggesting that the enzyme consists of two identical subunits. The enzyme could be identified as a glycoprotein by lectin-binding analysis and by the reduction of the molecular mass to 97,000 Da upon treatment of the denatured enzyme with endoglycosidase-F/N-glycosidase F. In its native form, however, the enzyme was only partially deglycosylated and retained full enzymatic activity. In addition to TRH, the enzyme also hydrolyzed L-5-oxoprolyl-beta-naphthylamide, and thus a convenient fluorimetric assay could be established to determine high enzyme activities. The hydrolysis of both substrates was found to obey Michaelis-Menten kinetics, but considerable differences in the respective Km and Vmax values were noticed.
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PMID:Purification and characterization of the thyrotropin-releasing-hormone-degrading ectoenzyme. 792 52

A 7 years 3 months old Japanese boy with familial thyroxine binding globulin (TBG) excess associated with growth hormone (GH) deficiency is reported. The patients height was 106.4 cm (-2.86 s.d.) and his bone age was 5 years and 3 months. He had no goiter and his developmental milestones were normal. The serum thyroid stimulating hormone (TSH) was 2.8 microU/mL, triiodothyronine (T3) 3.1 ng/mL, thyroxine (T4) 23.4 micrograms/dL and free T4 1.8 ng/dL. The serum TBG level was beyond 80.0 micrograms/mL, with normal TSH response to the thyrotropin-releasing hormone (TRH) test. Familial study revealed that his grandmother, mother, uncle, younger sister and younger brother had high TBG and T3 levels, thus an X-linked co-dominant transmission was suggested. The peak GH responses to insulin and clonidine hydrochloride were 5.8 and 8.2 ng/mL, respectively. The mean nocturnal GH concentration was 2.5 ng/mL. His growth velocity increased from 4.8 to 8.4 cm/year and his serum TBG levels decreased gradually after human growth hormone (hGH) treatment.
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PMID:A case of familial thyroxine binding globulin excess associated with growth hormone deficiency. 794 5

We examined whether the cholinergic mechanism is involved in the paradoxical GH responses to vasoactive intestinal peptide (VIP) and peptide histidine methionine (PHM) in acromegaly. 28 patients with active acromegaly underwent i.v. bolus injections of thyrotropin-releasing hormone (TRH, 500 micrograms), GH-releasing hormone (GHRH, 100 micrograms), VIP (100 micrograms), and PHM (100 micrograms) with or without a prior atropine treatment (1 mg, i.m., 30 min before). Blood samples were collected before and at intervals up to 120 min after the injection, and plasma GH levels were measured. In response to TRH, GHRH, VIP and PHM, 23 (82%), 24 (86%), 13 (46%) and 7 (25%) patients, respectively, responded with a significant GH increase (> 50% and 6 micrograms/l above the basal level). The effect of atropine pretreatment was examined in only these responders to the respective peptides. When the GH responses were estimated by the area under the response curve, the atropine pretreatment was able to significantly suppress the GH response to GHRH, but not to TRH, VIP, or PHM. Although the lack of cholinergic involvement in the TRH-induced GH release in acromegaly is confirmatory to previous reports, the same results with the VIP- and PHM-induced GH release are novel. The present study may suggest that in acromegaly the physiological GH response is mediated by the cholinergic mechanism, but the paradoxical ones are not.
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PMID:Lack of involvement of the cholinergic mechanism in vasoactive intestinal peptide- and peptide-histidine methionine-induced growth hormone (GH) responses in acromegaly: comparison with the GH responses to thyrotropin-releasing hormone and GH-releasing hormone. 799 Oct 70

Pituitary apoplexy often occurs spontaneously in adenomas. A few cases have been reported after testing anterior pituitary function by means of intravenous injections of a mixture of gonadotropin-releasing hormone and thyrotropin-releasing hormone, or gonadotropin-releasing hormone alone. In these cases the development of visual field defects has necessitated surgical intervention, which confirmed pituitary apoplexy. We describe a patient with a pituitary macroadenoma. He developed symptoms and signs of pituitary apoplexy immediately after intravenous injection of a mixture of hypothalamic releasing hormones. His visual fields remained normal, and he recovered spontaneously.
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PMID:[Pituitary apoplexy after injection of pituitary-hormone releasing hormones]. 807 63


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