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[Intermediate lobe of the amphibian pituitary gland: an endocrine gland with multiple secretions and under multi-hormonal control].
The cells of the frog pars intermedia synthesize a 36 000 (36K) protein called proopiomelanocortin (POMC). After [3H]glucosamine incorporation, separation of newly synthesized products by SDS-polyacrylamide gel electrophoresis showed that this 36K protein was glycosylated. Tryptic mapping revealed only one site of glycosylation and showed that the carbohydrate side-chain was located in the N-terminal region of POMC. The 36K protein was not released by the melanotrophs, but it generated, through specific intracellular proteolytic cleavage, a number of smaller peptides which were subsequently released. These peptides were identified by various methods including selective amino-acid incorporation, HPLC purification, acid-urea gel electrophoresis, tryptic and chymotryptic mapping, assay of melanotropic activity, radioimmunoassays and immunoprecipitations. Some of the newly synthesized N-terminal (18K) fragment of the POMC was secreted intact while a portion of it was further processed, via an intermediate peptide, to give mature gamma-MSH. All three of these peptides were glycosylated. In addition, the mature peptide (gamma-MSH) exhibited a low but significant melanotropic activity. The C-terminal portion of the prohormone was very rapidly processed to give des N alpha-acetyl alpha-MSH, corticotropin-like-intermediate lobe peptide (CLIP) and beta-endorphin. Authentic alpha-MSH was always absent in cellular extracts: acetylation to give rise to alpha-MSH was a late enzymatic process strictly linked to hormonal release. Since acetylation of alpha-MSH is required for full biological activity of this peptide, it is possible to conceive that this later step could be under neuroendocrine control. Using the perifusion technique we have been able to show the complexity of the control mechanisms regulating amphibian melanotrophs. It is generally accepted that the aminergic innervation of the intermediate lobe of the pituitary is involved in the hypothalamic control of melanotropin release. We have demonstrated that, in amphibians, dopamine inhibits alpha-MSH secretion through D2-type dopaminergic receptors whereas norepinephrine and (or) epinephrine stimulate alpha-MSH secretion via beta-adrenergic receptors. The existence of peptidergic fibers within parenchymal cells of the pars intermedia has been demonstrated. Evidence for TRH-containing fibers has been obtained by immunohistochemistry. Using a specific radioimmunoassay for TRH, we have confirmed the presence of TRH in the neurointermediate lobe of the frog. We have shown that TRH is a powerful MSH-releasing factor in these animals.(ABSTRACT TRUNCATED AT 400 WORDS)
[Immunocytochemical localization of alpha-melanotropin in bovine placenta].
The immunocytochemical study of the bovine placenta has demonstrated the presence of cells containing alphamelanotropic hormones, in the decidual epithelium, since the 4th month of pregnancy. The number and the staining intensity of those cells grow up with the placental development. Since the 6th month, we observed the immunoreactional presence of cells in the foetal chorionic epithelium.
A possible role for intermediate lobe peptides in the pathogenesis of idiopathic aldosteronism.
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Shigella sonnei endotoxin reduces arterial blood pressure but does not alter pituitary pro-opiocortin cleavage and corticosterone release in the rat.
Intravenous (iv) bolus injection of 320 and 640 micrograms/Kg of lipopolysaccharides (LPS) of S. sonnei (either in phase I or in phase II) resulted in a dose-dependent decrease in mean arterial pressure, when given in freely moving rats. No changes were observed in plasma beta-endorphin (beta-EP), ACTH and corticosterone levels. Pituitary beta-EP content was not modified 1 h after iv injection of LPS. Data suggest that doses of LPS, which are able to produce reversible hypotension, do not alter pro-opiocortin cleavage and corticosterone release.
[Opioid peptides].
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Post-translational processing of neuropeptide precursors.
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Brain peptides.
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Neuromodulatory functions of the brain pro-opiocortin system.
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New perspectives in neuropeptides. Biosynthesis from large precursors. The pro-opio-melanocortin model in the pars intermedia.
Although more and more is known about the nature of neuropeptides, there are two basic questions which need to be looked at in order for the neurophysiologists and the neuropharmacologists to have all the tools necessary for their studies. The first question is the site of biosynthesis of neuropeptides and the second is their biosynthetic pathway. We believe and propose that all neuropeptides will be formed from a larger molecular weight precursor similar to beta-LPH for beta-endorphin. All models of peptide hormones (pro-insulin, pro-PTH, pro-glucagon, beta-lipotropin etc.,) show the same characteristic preferential site of cleavage made of a double basic residue. This is also the type of cleavage recently described by Nakanishi et al. (1979). Using the rat pars intermedia, we showed that this tissue preferentially makes alpha-MSH and beta-endorphin from a large precursor, while beta-LPH and ACTH are short lived intermediates. All products of maturation were identified by chemical analyses leaving no doubt about their nature and identity. We strongly believe that the brain will biosynthesize beta-endorphin and possibly alpha-MSH in similar fashion. We also predict that our results will apply to the other neuropeptides which wil be formed from large precursors. These studies could be very useful in the interpretation of the intricate relationship between neuropeptides and behavioral effects.
Subcellular fractionation studies on the post-translational processing of pro-adrenocorticotropic hormone/endorphin in rat intermediate pituitary.
The subcellular localization of the post-translational processing steps which occur in the conversion of pro-adrenocorticotropic hormone (ACTH)/endorphin into beta-endorphin-sized molecules in rat intermediate pituitary has been studied. Primary cell cultures were incubated in radioactively labeled amino acids, and a subcellular fraction containing secretory granules was separated from a subcellular fraction containing rough endoplasmic reticulum and Golgi apparatus by centrifugation of homogenates on gradients on Percoll (Pharmacia Fine Chemicals). The radiolabeled beta-endorphin-related material in the granule and rough endoplasmic reticulum/Golgi apparatus fractions was quantitated by immunoprecipitation and sodium dodecyl sulfate polyacrylamide gel electrophoresis. A pulse-chase labeling experiment demonstrated that newly synthesized beta-endorphin-related material first appeared in the rough endoplasmic reticulum/Golgi apparatus fraction and after longer incubations (chase) appeared in the secretory granule fraction. After 2 h of chase incubation, about 85% of the beta-endorphin-related material synthesized during the 30-min pulse incubation had been transferred from the rough endoplasmic reticulum/Golgi apparatus to the secretory granule fraction. The conversion of most of the newly synthesized pro-ACTH/endorphin into beta-lipotropin occurred in the rough endoplasmic reticulum/Golgi apparatus fraction, whereas the conversion of most of the beta-lipotropin into beta-endorphin-sized molecules occurred in the secretory granule fraction.
Evidence for intragranular processing of pro-opiocortin in the mouse pituitary intermediate lobe.
Mouse pituitary neurointermediate lobes were pulse-incubated in [3H] arginine or [3H] lysine for 10 min and then chase-incubated for periods 0 to 4h. The labeled peptides from the lobes were analysed by immunoprecipitation with specific antisera, and thereafter, by acid-urea polyacrylamide gel electrophoresis. Using this paradigm, the synthesis of a prohormone common to adrenocorticotropin (ACTH) and endorphin was detected in 10 min pulse labeled lobes. Following a chase period, processing of the prohormone to several forms of ACTH (mol. wt. 25000, 23000, and 13000), beta-lipotropin and beta-endorphin was observed. To determine the intracellular site of processing of the prohormone, subcellular fractionation studies of labeled lobes were carried out. Analysis of the fractions from the pulse-labeled lobes revealed that the newly synthesized labeled prohormone was primarily localized in a granule-enriched fraction. In lobes that were pulsed and then chase-incubated for 1 h, there was a decrease in the amount of prohormone and an appearance of processed products in the granule-enriched fraction. In another paradigm, where the secretory granule-fraction was isolated from pulse-labeled lobes and then incubated in vitro for 6 h at pH 5.5, processing of the endogenous labeled prohormone within the isolated granule fraction was observed. These data suggest, that in the mouse neurointermediate lobe, the ACTH/endorphin prohormone (pro-opiocortin) is rapidly packaged into secretory granules after synthesis and processed intragranularly.
Multiple cellular forms of corticotrophs in surgically removed pituitary adenomas and periadenomatous tissue in Cushing's disease.
Transsphenoidally removed samples of pituitary adenomas from 14 patients with Cushing's disease and 5 patients with Nelson's syndrome always contained groups of uniform small ACTH-cells. Antibodies against the pro-opiocortin precursor fragments beta-endorphin, ACTH, and 16k-peptide recognized material in typical adenoma cells. A subpopulation of these cells, varying in number from sample to sample, specifically exhibited alpha-melanotropin immunoreactivity. Most periadenomatous samples showed signs of severe degeneration. Typical Crooke cells only occurred in samples from patients with Cushing's syndrome, but, with this exception, no clear differences between pituitaries of patients with Cushing's and Nelson's syndromes could be discerned. Two other forms of ACTH-immunoreactive cells were observed: rare, single, highly immunoreactive cells, with characteristics of both normal and Crooke cells, and numerous syncytial groups of cells in an advanced state of disintegration, presumably the remnants of hyperplastic follicles. The four different corticotrophs are characterized according to their fine structure and immunoreactivity in this study.
[Recent findings on ACTH].
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[ACTH, beta-endorphin, lipotropins, and other pro-opiocortin-derived peptides: a new family of hormones (author's transl)].
beta-Endorphin, a pituitary morphino-mimetic peptide, was identified in a culture medium derived from a human corticotropic adenoma. Secretion products from cultured human cells derived from a small-cell carcinoma of the lung were shown to contain a high molecular weight precursor analagous to pro-opiocortin: this molecule is a polypeptide of the order of 28,000 daltons the enzymatic processing of which leads to the coordinated and simultaneous release of different peptide fragments: ACTH, beta- and gamma-lipotropins, beta-endorphin, fragment 16 K and gamma 3-MSH. All these peptides have been identified in human plasma, and pituitary and non-pituitary tumor extracts. Their plasma concentrations vary in a parallel manner, beta-endorphin and a peptide very similar to beta-MSH have been detected in human hypothalamus.
[Ontogenesis of pro-opio-melano-cortin neurons in the rat].
Immunocytochemical study of the pro-opio-melano-cortin neurones in rat fetuses and newborns indicates that: 1) they appear precociously in the mediobasal hypothalamus, as early as day 13 of fetal development, that is to say 3 days before pro-opio-melano-cortin-containing pituitary cells; 2) between day 13 and day 17 they display synchronous changes in their intracellular patterns of immunoreactivity, arguing in favour of their cyclic secreting activity, which precedes the establishing of their projections; 3) beginning with day 18 until birth, the somatal immunoreactivity disappears transitorily; during the same period and the first postnatal days, their immunoreactive fibres extend in various brain regions.
Structural organization of the corticotropin-beta-lipotropin precursor gene.
The human and the bovine corticotropin (ACTH)-beta-lipotropin (LPH) precursor gene have been isolated and characterized. Both genes consist of three exons which are divided by two large introns at exactly the same positions. One of the introns is inserted within the segment transcribed into the 5'-untranslated region of the mRNA, and the other interrupts the protein-coding sequence near the signal peptide region. The largest exon encodes most of the protein sequence which includes the three repeated melanotropin (MSH) peptides and other biologically active peptides such as ACTH and beta-endorphin. Thus, there is no apparent correspondence between the repetitive structure of the precursor protein and the structural organization of its gene. Comparison of the nucleotide sequences of the human and the bovine gene reveals that three regions are highly conserved, i.e., the region extending from the signal peptide to gamma-MSH, the ACTH region and the beta-MSH/beta-endorphin region. This suggests that the peptide(s) in the amino-terminal region, including gamma-MSH, may be of physiological importance, as is the case for ACTH and beta-endorphin. The different biologically active component peptides of the ACTH-beta-LPH precursor, encoded by a single gene, seem to be involved in the defense mechanism of the living organism by acting coordinately in the central nervous system as well as in peripheral tissues. The identification of the mRNA encoding the ACTH-beta-LPH precursor in a human ectopic ACTH-producing tumor is also reported.
[Mechanism of hormone production in ACTH-producing tumor].
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