Interactions of adrenocorticotropic hormone with its adrenal receptors. Degradation of ACTH-1-24 and ACTH-11-24.
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Abstract:
Crude membranes (20,000 x g pellet) prepared from human, rat, and ovine adrenals bind 1251-corticotropin-(l-24)tetracosapeptide (rz51-ACTH1-& and degrade unbound hormone.The degradation is dependent on temperature and the concentration of membrane proteins.The degradation of 1251-[9-tryptophan(o-nitrophenylsulfenyl)] -corticotropin -(1 -24) -tetracosapeptide (rz51 -NPS -ACTHI-21) is similar to 1251-ACTH1-24, but that of 1251-corticotropin-(11-24)-tetradecapeptide (1251-ACTH11-24) is larger.The degradation of 1251-ACTH1-24 is inhibited by ACTH1-24 and corticotropin-( 1 -IO)-decapeptide (ACTH&, but ACTHll-z4 at the same molar concentration has no effect.On the other hand, the degradation of 1251-ACTH11W2, is protected by ACTHll-24 and ACTHI-24, but not by ACTHlmlO.This suggests two systems of degradation, one will have the NH2-terminal sequence of ACTH,-2, as substrate, and the other the 11-24 COOH-terminal sequence.The main labeled product from the degradation of the 1251-ACTH1-24 and 1251-ACTH11-2, behaves as [1251]monoiodotyrosine on Sephadex G-50 and paper chromatography.The independence of ACTH binding to its receptor and degradation is demonstrated by the following facts.(a) Calcium and pancreatic trypsin inhibitor completely inhibit the binding at concentrations when the degradation is not altered; (b) the sequences of peptides of ACTH which inhibit the binding and degradation of 1251-ACTH,.24 are different.Keywords:
ACTH receptor
Corticotropic cell
The physiologic role of adrenocorticotropic hormone (ACTH) and its part in the pituitary—adrenal axis is one of the most intensively studied systems in endocrinology. ACTH was one of the first hormones that was found to stimulate cAMP production by the adrenal gland (1), and the notion that this effect was mediated via a specific cell surface receptor was confirmed by the elegant studies of Lefkowitz and colleagues (2) in work that set a standard for receptor characterization. Nevertheless, progress on the understanding of the ACTH receptor has been relatively slow. It is now clear that the MC2-R is synonymous with the ACTH receptor, and both terms are used in this chapter. In general, the term ACTH receptor is used to describe the functional entity for example, ligand binding to adrenal cells, whereas the term MC2-R is used to describe aspects that can clearly be related to this gene.
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Abstract The ACTH receptor (ACTH-R) is the second member of the melanocortin (MC-2) receptor family that includes five seven-transmembrane G protein-coupled receptors and has been shown to be predominantly expressed in the adrenal cortex. It has been postulated that ACTH may regulate its own secretion through ultra-short-loop feedback within the pituitary. ACTH-secreting adenomas are characterized by resistance to glucocorticoid feedback, and they may have dysregulated ACTH feedback. We therefore investigated the ACTH-R in normal and adenomatous human pituitary tissue. We report here the identification of ACTH-R mRNA in the human pituitary gland, which was confirmed by direct sequencing. We studied the expression of the ACTH-R in 23 normal pituitary specimens and 53 pituitary adenomas (22 ACTH-secreting, nine GH-secreting, eight prolactin-secreting, one TSH-secreting, one FSH-secreting, 10 nonfunctioning, and two silent corticotroph adenomas), using the sensitive technique of real-time quantitative PCR. Contamination of ACTH-secreting adenomas and nonfunctioning pituitary adenomas with nonadenomatous tissue was excluded by lack of Pit-1 expression. ACTH-R mRNA was detected in all normal pituitary specimens, and in situ hybridization colocalized expression to ACTH staining cells only. However, ACTH-R mRNA levels were undetectable in 16 of 22 ACTH-secreting tumors and in both silent corticotroph tumors. Diagnostic preoperative plasma ACTH levels were significantly lower in the ACTH-R positive ACTH-secreting tumors, compared with those who were ACTH-R negative (P = 0.0006). Direct sequencing of the coding region of the ACTH-R in cDNA from three ACTH-secreting tumors positively expressing the receptor showed no mutations, as did sequencing of genomic DNA in three receptor negative ACTH-secreting tumors and the two silent corticotrophs. These results provide further evidence compatible with an ACTH feedback loop in the pituitary and suggest that loss of expression of the ACTH-R in corticotroph adenomas of patients with Cushing’s disease may play a role in the resistance to feedback of the pituitary-adrenal axis seen in these patients.
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Pituitary neoplasm
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Crude membranes (20,000 x g pellet) prepared from human, rat, and ovine adrenals bind 1251-corticotropin-(l-24)tetracosapeptide (rz51-ACTH1-& and degrade unbound hormone.The degradation is dependent on temperature and the concentration of membrane proteins.The degradation of 1251-[9-tryptophan(o-nitrophenylsulfenyl)] -corticotropin -(1 -24) -tetracosapeptide (rz51 -NPS -ACTHI-21) is similar to 1251-ACTH1-24, but that of 1251-corticotropin-(11-24)-tetradecapeptide (1251-ACTH11-24) is larger.The degradation of 1251-ACTH1-24 is inhibited by ACTH1-24 and corticotropin-( 1 -IO)-decapeptide (ACTH&, but ACTHll-z4 at the same molar concentration has no effect.On the other hand, the degradation of 1251-ACTH11W2, is protected by ACTHll-24 and ACTHI-24, but not by ACTHlmlO.This suggests two systems of degradation, one will have the NH2-terminal sequence of ACTH,-2, as substrate, and the other the 11-24 COOH-terminal sequence.The main labeled product from the degradation of the 1251-ACTH1-24 and 1251-ACTH11-2, behaves as [1251]monoiodotyrosine on Sephadex G-50 and paper chromatography.The independence of ACTH binding to its receptor and degradation is demonstrated by the following facts.(a) Calcium and pancreatic trypsin inhibitor completely inhibit the binding at concentrations when the degradation is not altered; (b) the sequences of peptides of ACTH which inhibit the binding and degradation of 1251-ACTH,.24 are different.
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A 47-year-old woman presented with a pituitary microadenoma manifesting as typical Cushing's syndrome. The diagnosis was Cushing's disease based on the endocrinological findings. Plasma adrenocorticotropic hormone (ACTH) levels were greatly increased from 66 pg/ml to 2490 pg/ml (about 38-fold) in response to the administration of 100 μg human growth hormone-releasing peptide (GHRP)-2. GHRP receptor type 1a messenger ribonucleic acid was detected in the tumor. Therefore, GHRP-2 may stimulate ACTH via the GHRP receptor type 1a in pituitary ACTH-producing tumor. The GHRP-2 test, currently clinically available in Japan, may be a useful diagnostic tool for Cushing's disease.
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Adrenocorticotropic hormone (ACTH) is a tropic hormone produced by the anterior pituitary. The hypothalamic-pituitary axis controls it. ACTH regulates cortisol and androgen production. Diseases associated with ACTH include Addison disease, Cushing syndrome and Cushing disease.
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Adrenocorticotropic hormone (ACTH ) is a hormone produced by the pituitary gland that stimulates the production of cortisol. Cortisol is a steroid hormone produced by the adrenal glands that is important for regulating glucose, protein, and lipid metabolism; suppressing the immune system's response; and helping to maintain blood pressure. This process of stimulating ACTH production in the pituitary is done via the hypothalamic-pituitary-adrenal axis (HPA ). Laboratory evaluation of ACTH can be assessed by ACTH . For most accurate results, testing should be done between 6 and 10 a.m. ACTH laboratory tests require a special refrigerated centrifuge to immediately separate plasma from cells, then the specimen needs to be immediately frozen. ACTH concentrations vary considerably depending on physiologic conditions and therefore should always be evaluated simultaneously with cortisol. Different assay methods can vary and cannot be used interchangeably. ACTH can also be measured as part of the ACTH stimulation test.
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✓ The authors report a case in which a patient harbored a corticotroph macroadenoma that secreted biologically inactive high-molecular-weight adrenocorticotropic hormone (ACTH) as well as authentic ACTH 1–39. The secretion of the high-molecular-weight ACTH was determined using gel chromatography. The authors believe that these two molecules competed with each other at the ACTH receptor and, thus, the bioactivity of ACTH 1–39 was masked and Cushing features were not manifested in the patient. This type of silent corticotroph adenoma may be categorized as a clinically nonfunctioning adenoma. Plasmas from patients with silent corticotroph adenomas, which are identified by positive immunohistochemical staining of ACTH, should be frozen, stored, and analyzed using gel chromatography to examine whether the tumors produce and secrete high-molecular-weight ACTH.
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