Adrenocorticotropic hormone specificity

FIGURE 1 8-5 Tissue-specific processing of the pro-opiomelanocortin (POMC) precursor yields a wide array of bioactive peptide products. Processing of the POMC precursor varies in various tissues. In anterior pituitary, adrenocorticotropic hormone (ACTH (1-39)) and P-1 ipo tropin (P-LPH) are the primary products of post-translational processing. Arcuate neurons produce the potent opiate P-endorphin (P-endo (1-31)) as well as ACTIK1 -13) NIT,. Intermediate pituitary produces a-melanocyte-stimulating hormone (aMSH), acetylated P endof 1 31) and P-endo(l-27). NTS, nucleus tractus solitarius. 

FIGURE 18-7 Processing of the proopiomelanocortin (POMC) precursor proceeds in an ordered, stepwise fashion. Cleavage of the POMC precursor occurs at seven sites, with some of the reactions being tissue-specific. The circled numbers indicate the temporal order of cleavage in tissues where these proteolytic events occur. ACTH, adrenocorticotropic hormone CLIP, corticotropin-like intermediate lobe peptide JP, joining peptide LPH, lipotropin MSH, melanocyte-stimulating hormone PC, prohormone convertase. 

FIGURE 23-3 Radioimmunoassay (RIA). (a) A low concentration of radiolabeled hormone (red) is incubated with (T) a fixed amount of antibody specific for that hormone or (2) a fixed amount of antibody and various concentrations of unlabeled hormone (blue). In the latter case, unlabeled hormone competes with labeled hormone for binding to the antibody the amount of labeled hormone bound varies inversely with the concentration of unlabeled hormone present, (b) A radioimmunoassay for adrenocorticotropic hormone (ACTH). A standard curve of the ratio [bound] to [unbound radiolabeled ACTH] vs. [unlabeled ACTH added] is constructed and used to determine the amount of (unlabeled) ACTH in an unknown sample. If an aliquot containing an unknown quantity of unlabeled hormone gives, say, a value of 0.4 for the ratio [bound]/[unbound] (see arrow), the aliquot must contain about 20 pg of ACTH. 

The primary glucocorticoid released in humans is cortisol (also known as hydrocortisone). Cortisol synthesis and secretion are under the control of specific hypothalamic and pituitary hormones.7,24 31 Corticotropinreleasing hormone (CRH) from the hypothalamus stimulates the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH travels in the systemic circulation to reach the adrenal cortex, where it stimulates cortisol synthesis. Cortisol then travels in the bloodstream to various target tissues to exert a number of physiologic effects (see Physiologic Effects of Glucocorticoids, later). 

Several of the small physiologically active peptides now are known to be derived from a single protein precursor synthesized by the pituitary gland (43). As shown in Figure 9, ACTH (adrenocorticotropic hormone), /3-LPH ( -lipotropic hormone), /3-MSH ( -melanocyte-stimulating hormone), /3-endorphin, and enkephalin result from the specific proteolytic cleavage of a precursor protein of approximately 8,000 daltons. 

The glucocorticoid cortisol is secreted from the adrenal cortex as a stress response under the control of adrenocorticotropic hormone (ACTH, corticotropin) produced by the anterior pituitary. Cortisol promotes catabolism by inducing synthesis of specific proteins. Cortisol binds to a cytosolic cortisol receptor which then translocates to the nucleus and switches on the expression of specific genes, notably that for PEP carboxykinase (PEPCK). Cortisol-induced expression of the key gluconeogenesis enzyme PEPCK increases levels of the enzyme and hence increases gluconeogenesis and available blood glucose. The cAMP-and cortisol-mediated pathways for induction of PEPCK expression are further linked by CREB-dependent expression of a coactivator protein PGC-1 that promotes cortisol-dependent expression of PEPCK. 

With the introduction and use of monoclonal antibodies, the measurement of hormones is now accurate and precise. The production of hormones in cancer involves two separate routes. First, the endocrine tissue that normally produces it can produce excess amounts of a hormone. Second, a hormone may be produced at a distant site by a non-endocrine tissue that normally does not produce the hormone. The latter condition is called ectopic syndrome. For example, the production of adrenocorticotropic hormone (ACTH) is norraotopic by the pituitary and is ectopic by the small cell of the lung. Consequently, elevation of a given hormone is not diagnostic of a specific tumor, because a hormone may be produced by a variety of cancers. 

FIGURE 10.43 Distribution of markers in typicai iung carcinoid. CgA, chromogranin A NSE, neuron-specific enoiase SYN, syn-aptophysin ACTH (b), big adrenocorticotropic hormone GRP, gastrin-reieasing peptide CK, cytokeratin CT, caicitonin CEA(m), monocionai carcinoembryonic antigen. 

The drug is a purely synthetic compound which possesses a distinct unique characteristic feature of inhibiting 11 -P-hydroxylation in the biosynthesis of cortisol, corticosterone and aldosterone. Therefore, it is invariably employed to test for hypothalamic-pituitary function. However, in the normal individual, the drug essentially blocks the specific enzymatic step that ultimately leads to the synthesis of cortisol and corticosterone in vivo), causing an absolute intense stimulation of adrenocorticotropic hormone (ACTH) secretion and inducing thereby a marked and pronounced enhancement in the urinary excretion of 17-hydroxy-corticosteroids. 

Corticotropin, adrenocorticotropln, adrenocorticotropic hormone, ACTH a polypeptide hormone secreted by the pituitary. The primary structure of the human hormone is Ser-T -Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-Gly-Lys-Lys-Arg-Arg-Pro-Val-Lys-Val-Tyr-Pro-Asn-Gly-Ala-Glu-Asp-Glu-Leu-Glu-Phe, M, 4541. Only sequence 31-33 is species-specific. Biological activity is determined by the first (hxed) 20 amino acids. Sequence 1-13 is identical to that of a-melanotropin. 

The actions of hormones are very diverse. Some, e.g. glucagon, have specific and clearly defined effects on the metabolism of particular tissues. Others such as growth hormone and the sex hormones have more general effects on growth and development while the tropic hormones stimulate their target tissues to secrete further hormones. For example the adrenocorticotropic hormone (ACTH), which is produced in the anterior pituitary, promotes the synthesis and release of glucocorticoids by the adrenal cortex. A list of some of the hormones and their effects on metabolism is given in Table 24.1. 

TRF has been shown to be highly specific in the release of TSH, having no effect on the secretion of luteinizing hormone (LH), follicle stimulating hormone (FSH), adrenocorticotropic hormone (ACTH) in vivo or in vitro . Recently, Tashjian et al. have reported that TRF stimulates the release of prolactin (PRL) in vitro. These results have been confirmed by other laboratories. As in the case with TSH, the effect of TRF on the release of prolactin is inhibited by thyroxin. Although large amounts of TRF are required to achieve an effect in rats, it appears to be relatively more potent for the release of prolactin in man > °. 

Membrane-bound hormone receptors were detected in the late 1960s. The binding of insulin, glucagon, and epinephrine to isolated plasma membranes of the rat liver or to isolated fat cells and fat cell membranes has been reported (Tomasi et al., 1970 Rodbell et al., 1971 Cuatrecasas, 1971a,b Freychet et al., 1971 Dunnick and Marinetti, 1971). Species-specific interaction between growth hormones and erythrocyte membranes has been shown by Cambiaso et al. (1971). Lef-kowitz et al. (1971) have published a detailed description of the interaction of adrenocorticotropic hormone with its receptors in the adrenal cortex, which appears to be a membrane-associated interaction (Finn et al., 1972). The modes of action for polypeptide hormones and their receptors have been the subject of intense investigation, and a number of reviews on this subject have been published (Cuatrecasas, 1974 Kahn, 1975 Catt and Dufau, 1977). 

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