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)

Histidyl-proline diketopiperazine (His-Pro DKP) cells in the pancreas of human fetuses aged between 12 and 19 wk were localized by the indirect antibody-enzyme method on semithin sections. To study their fine structure, two techniques were used: a superimposition technique consisting of comparison of the same cells in semithin and electron microscopic preparations, and an immunocytochemical technique on ultrathin sections using the unlabeled antibody peroxidase-antiperoxidase method. Our results show that (a) the same cells are positive for both His-Pro DKP and glucagon/glicentin, (b) His-Pro DKP immunoreactive cells possess extremely electron-opaque secretory granules, implying that these cells correspond to the A cells, and (c) His-Pro DKP immunoreactivity is found over the secretory granules. We hypothesize that the two peptides His-Pro DKP and thyrotropin-releasing hormone (TRH) have independent origins, since TRH is found in the B cells.
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PMID:Histidyl-proline diketopiperazine (His-Pro DKP) immunoreactivity is present in the glucagon-containing cells of the human fetal pancreas. 310 58

Clinical benefits of thyrotropin-releasing hormone (TRH) were tested in wobbler mice, an animal model of motor neuron disease. After the disease was clinically recognized at 3-4 weeks, the animals were divided into two groups, each group consisting of 5 pairs of wobbler mice and normal littermates. TRH (50 mg/kg) and normal saline (NS) were injected intraperitoneally daily, 6 times per week for 9 weeks, in a double-blind study. Weekly assessments consisted of front paw grip strength, push walking, body weight, and semiquantitative grading. At the end of the trial, the brain and spinal cord were sampled to measure TRH and cyclo (His-Pro) concentrations. Progression of motor neuron disease was evident in wobbler mice, regardless of treatment. Descriptive semiquantitative gradings showed the tendency of improvement in TRH-treated wobbler mice. In saline-injected controls, TRH levels in the cervical spinal cord were significantly increased (P less than 0.01) in wobbler mice compared to littermates. However, with TRH treatment, there was no significant difference in TRH and cyclo (His-Pro) levels in any neural tissue between wobbler and controls. The lack of clinical benefits with TRH in wobbler mice may be due to increased TRH levels found in diseased spinal cord in murine motor neuron disease.
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PMID:Thyrotropin-releasing hormone (TRH) in murine motor neuron disease (the wobbler mouse). 310 58

Cyclo(His-Pro), or histidyl-proline diketopiperazine, is an endogenous cyclic dipeptide that is ubiquitously distributed in tissues and body fluids of both man and animals. This cyclic dipeptide is not only structurally related to thyrotropin-releasing hormone (TRH, pGlu-His-ProNH2), but it can also arise from TRH by the action of the enzyme pyroglutamate amino-peptidase (pGlu-peptidase). The data on the distribution of TRH, cyclo(His-Pro), and pGlu-peptidase under normal and abnormal conditions are summarized and potential relationships analyzed. We conclude that all of the cyclo(His-Pro) cannot be derived from TRH. Two additional sources of cyclo(His-Pro) are suggested. It is proposed that 29,247 molecular weight TRH prohormone, prepro TRH, which contains 5 copies of TRH sequence, can be processed to yield cyclo(His-Pro). Thus, both TRH and cyclo(His-Pro) share a common precursor, prepro[TRH/Cyclo(His-Pro)].
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PMID:Is all cyclo(His-Pro) derived from thyrotropin-releasing hormone? 311 25

Medullary sites inducing gastric acid secretion in response to microinjection of the stable analogue of thyrotropin-releasing hormone (TRH; RX 77368, pGlu-His-[3,3'-dimethyl]-Pro-NH2) were investigated in urethan-anesthetized rats. Gastric acid output was recorded every 2 min through a double gastric cannula constantly perfused with 0.9% saline solution maintained at pH 5.5 using an automatic titrator. Unilateral microinjection of RX 77368 (10-100 ng in 50-nl volume) into the dorsal vagal complex (DVC), the dorsal vagal nucleus and nucleus tractus solitarius, induced a significant dose-dependent stimulation of gastric acid secretion. The peak response occurred within 50 min and lasted over 1 h. Other medullary sites, including the lateral, dorsal, and parvocellular reticular nuclei; the medial longitudinal fasciculus; and the medial cuneate nucleus injected with RX 77368 (10-100 ng), were inactive. The TRH metabolites, TRH-OH and His-Pro diketopiperazine (100 ng), injected into the DVC did not influence gastric acid secretion. The stimulation of gastric acid secretion induced by DVC injection of TRH was abolished by vagotomy. These results demonstrate that 1) the DVC is an important site of action for TRH-induced stimulation of gastric acid secretion, 2) TRH action in the DVC is not secondary to the formation of TRH metabolites, and 3) the effect is expressed by vagal efferent pathways. These findings added to the high concentration of TRH-immunoreactivity and receptors in the DVC suggest a role for endogenous TRH in the regulation of vagal outflow to the stomach.
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PMID:TRH analogue, RX 77368, injected into dorsal vagal complex stimulates gastric secretion in rats. 312 48

Brain and spinal sites of action of the stable thyrotropin-releasing hormone (TRH) analogue, RX 77368 [pGlu-His-(3,3'-dimethyl)-Pro-NH2], for stimulation of gastric acid secretion have been investigated in urethane-anesthetized rats with gastric fistula. RX 77368 microinjected at a 7.7-pmol dose into the dorsal vagal complex or nucleus ambiguus stimulated gastric acid secretion to 62.2 +/- 15.9 and 45.3 +/- 14.3 mumol/h, respectively, whereas in the vehicle-treated group acid secretion was 0.5 +/- 1.0 mumol/h. A 10-fold higher dose of RX 77368 was inefficient when microinjected into the medial septum, central amygdala, or lateral hypothalamus. The gastric secretory response to microinjection of RX 77368 into the nucleus ambiguus was dose related (0.7-77 pmol), long-lasting (greater than 90 min), and blocked by vagotomy. TRH (144 pmol) injected into the nucleus ambiguus also stimulated gastric acid secretion but was less potent than the stable TRH analogue, whereas the unrelated peptide, oxytocin, was inactive. Intrathecal injection of RX 77368 at doses up to 2500 pmol did not modify gastric acid secretion. These results demonstrate that the dorsal vagal complex and nucleus ambiguus are TRH sites of action for stimulation of gastric acid secretion through vagal dependent pathways. These findings, added to the high concentrations of TRH-like immunoreactivity and receptors present in these nuclei, suggest a possible role of medullary TRH in the vagal regulation of gastric acid secretion.
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PMID:Medullary sites of action of the TRH analogue, RX 77368, for stimulation of gastric acid secretion in the rat. 314 Dec 37

Rat thyrotropin-releasing hormone prohormone (pro-TRH) contains five separate copies of the TRH progenitor sequence: Gln-His-Pro-Gly. Each of the five sequences is flanked by pairs of basic residues and linked together by one of several predicted connecting sequences. Two of the pro-TRH-connecting peptides, prepro-TRH-(160-169) and prepro-TRH-(178-199), were detected in extracts of rat neural tissues by radioimmunoassay using antibodies directed against the corresponding synthetic probes. Endogenous prepro-TRH-(160-169) and prepro-TRH-(178-199) were purified by gel exclusion chromatography, reverse-phase high pressure liquid chromatography, and ion-exchange chromatography. Structural identification of each peptide was achieved by chromatographic comparison with synthetic standards, immunological analysis, and tryptic mapping. Equimolar amounts of these connecting fragments were observed in hypothalamus and spinal cord. Quantification of TRH in spinal cord and hypothalamus extracts revealed the presence of 4.9-6.3 mol of TRH/mol of prepro-TRH-(178-199) and 4.4-6 mol of TRH/mol of prepro-TRH-(160-169), respectively. By using the indirect immunofluorescence technique, prepro-TRH-(178-199) immunoreactive cell bodies were found in the paraventricular nucleus of the hypothalamus, and a dense plexus of immunopositive nerve terminals was observed in the external zone of the median eminence, in a distribution similar to that described for TRH. These studies demonstrate that prepro-TRH-(160-169) and prepro-TRH-(178-199) are, together with TRH, predominant storage forms of the TRH precursor in hypothalamus and spinal cord, being present in molar ratios corresponding to those expected for a nearly complete processing of the prohormone molecule. The presence of pro-TRH-connecting peptides in various brain regions, including the median eminence, suggests that these peptides might act as neuromodulators in the central nervous system and/or neuroendocrine signals at the pituitary level. In the olfactory lobes, prepro-TRH is processed differently since a C-terminally extended form of TRH, prepro-TRH-(172-199), is found as a major end product along with lower but significant amounts of prepro-TRH-(178-199) and prepro-TRH-(160-169). The striking difference in pro-TRH processing patterns among the various tissues examined suggests differential regulating mechanisms for TRH and/or TRH-related activities.
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PMID:Processing of thyrotropin-releasing hormone prohormone (pro-TRH) generates pro-TRH-connecting peptides. Identification and characterization of prepro-TRH-(160-169) and prepro-TRH-(178-199) in the rat nervous system. 314 16

In previous studies we have shown that thyrotropin-releasing hormone (TRH) antagonizes many of the neural effects of neurotensin (NT). This study, evaluated the ability of TRH and two TRH analogs: 3 methyl-His-TRH and Phe2-TRH to affect NT-induced miosis in rabbits. In confirmation of previous findings, NT (30 micrograms) produced a significant miosis. The high (60 micrograms), but not the low (30 micrograms) dose of TRH significantly antagonized NT (30 micrograms)-induced miosis. Of interest was the observation that 3 methyl-His-TRH and Phe2-TRH were more effective than native TRH in blocking NT-induced miosis. The inhibitory effect of 3 methyl-His-TRH on the miotic response to NT exhibited long duration (approximately 60 min) when compared to native TRH and Phe2-TRH. TRH or the TRH congeners had no appreciable effects on pupillary diameter when administered alone. These findings indicate that TRH antagonizes the miotic response to NT, and suggest a hitherto undescribed peptide-peptide interaction involved in regulation of iris motility.
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PMID:Antagonism of neurotensin induced miosis by thyrotropin-releasing hormone (TRH) in rabbits. 314 72

Cyclo(His-Pro), or histidyl-proline diketopiperazine, is a cyclic dipeptide endogenous to blood, cerebrospinal fluid (CSF), semen, brain, spinal cord, and gastrointestinal tract of humans. Although a part of cyclo(His-Pro) clearly appears to be derived from the limited proteolysis of thyrotropin-releasing hormone by Pyroglutamate aminopeptidase, the biosynthetic origin of the remainder of the peptide can only be speculated. The levels of this peptide in blood and CSF fluctuate in health and disease in a manner appropriate for a physiologically active endogenous molecule.
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PMID:Cyclo(His-Pro): its distribution, origin and function in the human. 328 38

Extracts from bovine pituitary were found to contain an activity catalyzing the conversion of glutaminyl peptides such as [Gln1]gonadotropin-releasing hormone, [Gln1, Gly4]thyrotropin-releasing hormone (H-Gln-His-Pro-Gly-OH), and H-Gln-Tyr-Ala-OH to the respective pyroglutamyl peptides. The TRH precursor fragment H-Lys-Arg-Gln-His-Pro-Gly-Lys-Arg-OH and the D-glutaminyl stereoisomer of H-Gln-Tyr-Ala-OH did not react under the same conditions. The conversion products were identified by Edman degradation, amino acid analysis, and reversed-phase HPLC. That this activity was exhibited by an enzyme, glutaminyl cyclase, was concluded from the protein character of the activity (revealed by its abolition with trypsin and heat), the Michaelis-Menten relationship between substrate concentration and conversion rate, and the substrate specificity. It was determined that glutaminyl cyclase had a molecular weight of 43,000-50,000, a pH optimum at pH 8, and Km and Vmax values in the range of 60-130 microM and 390-690 pmol/microgram per hr, respectively. Glutaminyl cyclase was not observed to require ATP and could be inhibited with 1.0 M ammonium chloride, which increased the Km and decreased the Vmax value. The subcellular distribution of glutaminyl cyclase corresponded to the one of peptidylglycine alpha-amidating monooxygenase believed to catalyze C-terminal amidations during posttranslational precursor processing. It was also observed that the formation of pyroglutamyl from glutaminyl peptides occurred nonenzymatically; however, the enzymatic reaction carried out with crude extract was found to be approximately 70 times faster than the nonenzymatic reaction enhanced by phosphate. It is speculated that glutaminyl cyclase may participate in the posttranslational processing of hormonal precursors to pyroglutamyl peptides.
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PMID:Identification of a mammalian glutaminyl cyclase converting glutaminyl into pyroglutamyl peptides. 347 73

We explored the effect of cyclo(His-Pro) on drinking in water-deprived rats. Intraventricular administration of cyclo(His-Pro) significantly reduced water intake in these rats in a dose-dependent fashion (3 X 10(-10) -3 X 10(-8) mole), whereas its intraperitoneal injection did not cause any effect on water intake. The inhibitory potency of cyclo(His-Pro) was found to be similar to that of thyrotropin-releasing hormone (TRH), but cyclo(His-Pro) did not significantly interfere with TRH binding in the rat brain. The data indicate that cyclo(His-Pro) action was not mediated through the TRH counterpart. These results suggest that cyclo(His-Pro) may play a potential role in the regulation of water intake in the rat brain.
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PMID:Intraventricular administration of cyclo(His-Pro), a metabolite of thyrotropin-releasing hormone (TRH), decreases water intake in the rat. 392 Jun 63


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