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)

The data of this work describe the presence in the rat liver of a thyrotropin-releasing hormone (TRH)-degrading particulate metal-containing pyroglutamate aminopeptidase of high molecular weight. Following the fractionation of liver homogenate in 0.25 M sucrose, solubilization of the particulate fraction with papain and gel filtration on ACA34, an enzyme activity was detected which converts TRH into pyroglutamic acid and histidyl-proline diketopiperazine (cyclo[His-Pro]; cHP). [L-Histidine-2,5-3H]TRH and [L-proline-2,3-3H]TRH were used as a tracer. Products formed were separated by thin-layer chromatography, localized and quantified by scanning for radioactivity. Enzyme activities were tested using preferential site-directed inhibitors. Particulate pyroglutamate aminopeptidase activity was found to be sensitive to chelating agents. The physicochemical properties of this particulate aminopeptidase were distinct from the soluble pyroglutamate aminopeptidase from the same source. The particulate enzyme shared several similarities with particulate pyroglutamate aminopeptidase from adenohypophysis, brain and with serum enzyme, reported to have narrower specificity for TRH compared to the soluble pyroglutamate aminopeptidase from several tissues. The Km of the gel-filtrated enzyme is 27 microM and the specific activity 306 pmol.min-1.mg protein-1. Although no definite role has been established for this enzyme, it might be a potential determinant of cHP concentrations in liver. Furthermore, cHP is known to possess biological activities and specific binding sites in liver membranes. One of the major sites for TRH breakdown in vivo, the liver, probably represents a target tissue for TRH, especially for pancreatic TRH, and the particulate enzyme involved in the conversion of TRH into cHP may assume a specific function.
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PMID:Presence of a particulate thyrotropin-releasing hormone-degrading pyroglutamate aminopeptidase activity in rat liver. 256 31

The influence of intracerebroventricularly (ICV) administered thyrotropin-releasing hormone pGlu-His-Pro-NH2 (TRH), pGlu-His-Phe-NH2 (TRH analog, (TRHa)), Met-Glu-His-Phe(ACTH-(4-7)) and His-Phe-Arg-Trp-Gly (ACTH-(6-10)) on autoregulation of cerebral blood flow was studied in anesthetized, ventilated rats. Autoregulatory capacity of the cerebrovascular bed was tested by hypothalamic blood flow (HBF) and total cerebral blood volume (CBV) determinations during consecutive stepwise lowering of the systemic mean arterial pressure to 80, 60 and 40 mmHg, by hemorrhage. None of the peptides caused a change in resting HBF or CBV upon ICV administration (5 micrograms/kg). However, the same dose of TRH, TRHa and ACTH-(4-7) resulted in impairment of autoregulation. ACTH-(6-10) was not effective. Thus, the disturbed autoregulation may be due to the presence of the dipeptide Glu-His which is common to TRH, TRHa and ACTH-(4-7).
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PMID:Naloxone-like influence of TRH and ACTH-(4-7) on hypothalamic blood flow autoregulation in the rat. 283 22

The abilities of 4 triazolobenzodiazepines, adinazolam, alprazolam, estazolam and triazolam, to inhibit thyrotropin-releasing hormone (TRH) receptor binding and to antagonize the narcoleptic effects of TRH were examined. The IC50 values for inhibition of 3H-3-methyl-His-2-TRH (MeTRH) binding ranged from 19 microM to 477 microM, and the Hill coefficient from 0.53 to 0.98. Similar ranges of values were obtained from benzodiazepines of other structural classes. Thus, the inhibition of TRH receptor binding by the triazolobenzodiazepines is similar to that produced by other types of benzodiazepines. Furthermore, the triazolobenzodiazepine, alprazolam, antagonized the narcoleptic effect of TRH. However, this action is not necessarily linked to its inhibition of TRH receptor binding since alprazolam also inhibited the narcoleptic effect of amphetamine.
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PMID:Inhibition of the binding and the behavioral effects of thyrotropin-releasing hormone (TRH) by the triazolobenzodiazepines. 284 42

Neurons located in the medial septum-nucleus of the diagonal band of Broca (vertical limb) and antidromically activated by electrical stimulation of the fimbria were recorded in urethane anesthetized rats. Forty-three percent of these septohippocampal neurons (SHNs) were excited by the iontophoretic application of thyrotropin-releasing hormone (TRH). Rhythmically bursting SHNs were more often excited (63%) by TRH than the non-bursting SHNs (35%). The majority of the TRH-sensitive SHNs could also be excited by cholinergic agonists. TRH-induced excitations were not abolished by the simultaneous application of atropine. Potentiation by TRH of acetylcholine, carbachol or glutamate-induced excitations of SHNs were rarely observed. Cyclo (His-Pro) and (3-Me-His2)-TRH were observed to have similar, although less dramatic, effects. These results demonstrate that the SHNs, which are the neurons of origin of the septohippocampal pathway, are readily excited by TRH.
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PMID:Effects of TRH, cyclo-(His-Pro) and (3-Me-His2)TRH on identified septohippocampal neurons in the rat. 285 93

Pyroglutamate aminopeptidase, which catalyzes metabolism of thyrotropin-releasing hormone (TRH) to cyclo(His-Pro), is the major enzyme of TRH metabolism in human CSF. The partially purified CSF pyroglutamate aminopeptidase has a pH optimum between 6.0 and 7.4, and a Km of 15.9 +/- 3.1 microM. A number of potential competitive inhibitors of the enzymatic activity were examined, of which luteinizing hormone-releasing hormone and bombesin were the most effective. An examination of the structure of various peptides that inhibit pyroglutamate aminopeptidase activity indicated that the enzyme generally prefers a substrate having amino-terminal pyroglutamic acid (pGlu) and a COOH-terminal that is either blocked or distant from amino-terminal pGlu. Heavy metals, EDTA and reducing agents inactivated the enyzme, whereas benzamidine, phenylmethylsulfonylfluoride, trypsin inhibitor and alkylating agents had little or no effect on the enzymatic activity. Thiol-oxidizing agent 5,5'-dithiobis(2-nitrobenzoic acid), however, considerally inhibited the enzymatic activity. We hypothesize that CSF pyroglutamate aminopeptidase may play a role in the biologic actions of TRH.
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PMID:Metabolism of thyrotropin-releasing hormone in human cerebrospinal fluid. Isolation and characterization of pyroglutamate aminopeptidase activity. 286 82

The degradation of thyrotropin-releasing hormone in rat brain homogenates was studied in the presence of N-benzyloxycarbonyl-prolyl-prolinal and pyroglutamyl diazomethyl ketone, specific and potent active-site-directed inhibitors of prolyl endopeptidase and pyroglutamyl peptide hydrolase, respectively. Substantial TRH degradation was observed, suggesting the presence of another thyrotropin-releasing hormone-degrading enzyme(s). Reports of a thyrotropin-releasing hormone-degrading enzyme with narrow specificity that cleaves the pGlu-His bond of this tripeptide led us to develop a coupled assay using pGlu-His-Pro-2NA as the substrate to measure this activity. Cleavage of the pGlu-His bond of this substrate under conditions in which pyroglutamyl peptide hydrolase is not expressed occurred in the particulate fraction of a rat brain homogenate. This particulate pyroglutamyl-peptide cleaving enzyme was not inhibited by pyroglutamyl diazomethyl ketone but was inhibited by metal chelators such as EDTA and o-phenanthroline. The particulate pyroglutamyl-peptide cleaving enzyme was found predominantly in the brain. Activity in brain regions varied widely with highest levels present in cortex and hippocampus and very low levels in pituitary. The data suggest that degradation of thyrotropin-releasing hormone by the particulate fraction of a brain homogenate is catalyzed mainly by an enzyme that cleaves the pGlu-His bond of thyrotropin-releasing hormone but is distinct from pyroglutamyl peptide hydrolase.
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PMID:Delineation of a particulate thyrotropin-releasing hormone-degrading enzyme in rat brain by the use of specific inhibitors of prolyl endopeptidase and pyroglutamyl peptide hydrolase. 286 8

The distribution of cyclo(His-Pro), thyrotropin-releasing hormone and pyroglutamate aminopeptidase activity was examined in the CSF of human and a number of other mammalian species. Cyclo(His-Pro)-like immunoreactivity was present in the CSF of all species examined, and was immunologically and chromatographically identical with the authentic cyclo(His-Pro). Cyclo(His-Pro) concentration in CSF had no significant correlation with CSF TRH or pyroglutamate aminopeptidase.
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PMID:Distribution and characterization of cyclo(His-Pro)-like immunoreactivity in human cerebrospinal fluid. 287 37

Previous studies have shown that intracisternal (i.c.), but not intravenous administration of thyrotropin-releasing hormone (TRH), an endogenous tripeptide (pGlu-His-Pro-NH2), produces a time-, dose-dependent and vagus-mediated stimulation of acid secretion in rats. This study was designed to test the hypothesis that endogenous brain TRH plays a role in regulation of acid secretion in the pylorus-ligation model. In confirmation of previous reports, i.c. TRH (1 microgram) significantly (P less than 0.01) stimulated gastric acid output, gastric secretory volume and decreased gastric intraluminal pH. Intracerebroventricular (i.c.v.) infusion of TRH antiserum (anti-TRH) 30 min prior to pyloric occlusion significantly reduced acid output, secretory volume and raised gastric pH. This inhibitory gastric acid secretory response to i.c.v. anti-TRH appears to be specific since i.c.v. infusion of normal rabbit serum or antisera raised against neurotensin (NT), Leu-enkephalin (L-enk), gonadotropin-releasing hormone (GnRH), somatostatin (SRIF) and alpha-melanocyte stimulating hormone (alpha-MSH) were without measurable effect. The findings of this study indicate that endogenous brain TRH, but not NT, L-enk, GnRH, SRIF or alpha-MSH plays a physiological role in regulation of acid secretion.
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PMID:Inhibition of gastric acid secretion by immunoneutralization of endogenous brain thyrotropin-releasing hormone. 288 Jun 45

Levels of thyrotropin-releasing hormone (TRH) - and cyclo(His-Pro) (CHP)-like immunoreactivities and the activity of enzyme Pyroglutamate aminopeptidase (PAPase) were measured in cerebrospinal fluid (CSF) of over 100 normal adults (NA) and infants, and adult patients with various neurologic and neuropsychiatric disorders (NNDA). Levels of TRH and CHP in CSF of over 70% of the NA group were below 50 and 500 pg/ml respectively. The TRH- and CHP-like immunoreactivities in the remainder of the 30% of NA specimens exhibiting higher peptide concentrations were enzymatically and chromatographically characterized and were found to behave like authentic peptides. The levels of both of these peptides were significantly elevated in the CSF of most of the NNDA patients. An elevation in the CSF level of CHP was significantly correlated with the level of TRH, but not PAPase. Results from this study suggest that CSF elevation of TRH level may be due to a nonspecific response to stress that may be associated with hospitalization, myelogram procedure, and/or the neurologic and neuropsychiatric diseases for which the patients were admitted.
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PMID:Thyrotropin-releasing hormone and cyclo (His-Pro)-like immunoreactivities in the cerebrospinal fluids of 'normal' infants and adults, and patients with various neuropsychiatric and neurologic disorders. 289 Oct 13

We employed quantitative autoradiography to examine the distribution of thyrotropin-releasing hormone (TRH) receptors in the rat CNS. The binding of [3H]3-methyl-histidine-TRH [( 3H]MeTRH) to TRH receptors in frozen rat brain sections was saturable, of a high affinity (Kd = 5 nM), and specific for TRH analogs. Autoradiograms of [3H]MeTRH binding showed highest concentrations of TRH receptors in the rhinencephalon, including accessory olfactory bulb, nuclei of the amygdala, and the ventral dentate gyrus and subiculum of the hippocampus. Moderate TRH receptor concentrations were found within the thalamus and hypothalamus, in most regions of the rhombencephalon, such as the cranial nerve nuclei, and in the substantia gelatinosa of the spinal cord. Neocortex and basal ganglia contained low densities of TRH receptors. This distribution correlates well with the sensitivity of brain regions to the known effects of TRH, and suggests that TRH receptors may mediate the actions of TRH in the rat CNS.
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PMID:Autoradiographic localization of thyrotropin-releasing hormone receptors in the rat central nervous system. 298 Dec 97


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