Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Corticostatic peptides are a family of arginine-rich cysteine-rich peptides that inhibit ACTH-stimulated corticosterone (B) production in rat adrenal cell suspensions. In this communication we describe a new method for the facile isolation and purification of these basic peptides from rabbit adult lung. We then describe the isolation and sequences of the four rabbit peptides, CSI, CSII, CSIII, and CSIV, and compare their biological activities in the ACTH (150 pg/ml) inhibition assay. CSI is by far the most potent of the four peptides. Using CSI as a model, we then studied its effects on the proximal and distal parts of the pathway leading to the generation of cAMP. CSI had no effect on (Bu)2cAMP action on forskolin or cholera toxin in their ability to mimic ACTH and increase B production in rat adrenal cells, nor did CSI have any effect on the stimulation of B production by pertussis toxin. Endogenous cAMP stimulated by ACTH decreased after the addition of CSI, which pointed to the inhibition of ACTH binding to explain the mode of action of this corticostatin. Displacement of the specific binding of labeled ACTH by CSI and the ACTH antagonist ACTH-(6-24) was determined, and indeed, CSI did displace ACTH from its binding site. The question of what portion of the ACTH molecule was involved in the action of CSI was answered by studying ACTH-(1-13) acetyl amide (alpha MSH) and ACTH-(1-18) amide. CSI had no effect on alpha MSH stimulation of B production, but did lower the production of B stimulated by ACTH-(1-18) amide. Therefore, CSI must act on ACTH-(14-18), which is part of the so-called address region of ACTH, which is -Gly14-Lys15-Lys16-Arg17-Arg18-, the very basic part of the molecule. These results indicate that CSI acts by competing with ACTH for its binding receptor on the adrenal cell and that this competition is confined to amino acids 14-18 of the molecule when it is bound to the receptor.
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PMID:Isolation and mode of action of rabbit corticostatic (antiadrenocorticotropin) peptides. 131 Dec 40

Interactions between signal transducing systems may be important in the integrated control of cellular processes in basal and hormonally regulated cells. The cultured bovine adrenal fasciculata cell provides a model to study the interactions between the cAMP and calcium-sensitive phospholipid dependent protein kinase C. In this study, angiotensin II (A-II) and phorbol ester (PMA) potentiated the stimulatory actions of ACTH in a dose-dependent manner on cAMP production. At maximal concentrations, A-II and PMA also potentiated the effects of cholera toxin and forskolin on cAMP production. Both staurosporine, a protein kinase C inhibitor, and desensitization of protein kinase C by a 24-h pretreatment with PMA blunted the effect of PMA, but only partially inhibited (34%) the effect of A-II. Neither nifedipine, a specific calcium channel antagonist, nor pretreatment of cells with pertussis toxin modified the amplifying effects of A-II or PMA. In contrast, trifluoperazine, a calmodulin inhibitor, reduced the potentiating effect of A-II by about 35%, but association with staurosporine blunted its effects. Moreover, the steroidogenic effects of ACTH plus A-II were more than additive, but this synergism was blunted in the presence of both inhibitors. In conclusion, PMA and A-II potentiated agonist-induced cAMP production by bovine adrenal fasciculata cells. The data suggest that the effects of PMA were mediated exclusively by protein kinase C, whereas those of A-II were mediated by both protein kinase C and calmodulin.
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PMID:Angiotensin II potentiates agonist-induced 3',5'-cyclic adenosine monophosphate production by cultured bovine adrenal cells through protein kinase C and calmodulin pathways. 133 Apr 96

A lipopolysaccharide from Pantoea agglomerans (LPSp) was purified and examined for relief of morphine dependence by observing its inhibition of the jumping of mice on naloxone-precipitate withdrawal. Administration of LPSp either intravenously or intradermally showed marked inhibition of the jumping. Beta-endorphin in mouse serum and brain tissue were recognized to be in synchrony with the time course of the relief. Administration of TNF-alpha gave similar effect, suggesting that LPSp induces a cytokine cascade to produce endogenous TNF followed by ACTH/beta-LPH gene products and beta-endorphin. The effect of LPSp was better than that of LPS from E. coli or Bordetella pertussis, and thus is considered to be applicable for clinical use.
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PMID:Inhibition of morphine dependence by a lipopolysaccharide from Pantoea agglomerans. 142 Oct 14

In addition to their steroidogenic effect on cultured bovine adrenal fasciculata cells ACTH and angiotensin-II (A-II) have a long term effect on the ability of these cells to respond to subsequent hormonal stimulation. The present work explores the effects of a 72-h pretreatment of adrenal cells with both hormones on the first steps of the mechanism of action of ACTH and A-II and on the amounts of the alpha-subunits of guanine nucleotide binding proteins Gs and Gi. ACTH but not A-II increased acute ACTH or cholera toxin-induced cAMP production. Moreover, ACTH but not A-II enhanced the amount of alpha S protein evaluated by cholera toxin ADP ribosylation, whereas both hormones elevated immunoblotted alpha S. Both hormones increased A-II induced phosphoinositide breakdown and Ca2+ uptake without modification of the A-II potentiating effect on ACTH-induced cAMP production. Treatment of cells with pertussis toxin (PT, 0.5 micrograms/ml) for the last 24 h reduced by 27% the A-II induced phosphoinositide breakdown in A-II pretreated cells but had no significant effect in ACTH-pretreated cells. No effect of PT was observed on A-II induced Ca2+ uptake or on its potentiating action on ACTH-induced cAMP production in ACTH as well as A-II-pretreated cells. Moreover, both hormones increased Gi proteins (40-41 kDa) evaluated by PT ADP ribosylation. Immunoblot analysis revealed that ACTH preferentially enhanced alpha i3, whereas the stimulatory effect of A-II was more marked on alpha i1 and alpha i2. These results indicate that in bovine adrenal fasciculata cells, peptide hormones settle target cell responsiveness not only by regulating the membrane-bound receptors, but also by modulating the level of G proteins coupling these receptors to the intracellular signals.
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PMID:Regulation of guanine nucleotide binding regulatory proteins in cultured adrenal cells by adrenocorticotropin and angiotensin-II. 164 63

An adrenal cGMP-stimulated phosphodiesterase (cGS-PDE) has been shown to mediate atrial natriuretic peptide (ANP)-induced reductions in aldosterone secretion and cAMP levels in primary bovine glomerulosa cells. High concentrations of cGS-PDE have been localized to the zona glomerulosa cell layer of the adrenal cortex using biochemical and immunological techniques. Immunoblot analysis using an affinity-purified, isozyme-specific antiserum revealed a single band that comigrated with a purified cGS-PDE (105 kDa) (1) and that was most highly concentrated in the outermost 1-2 mm of the cortex, representing the capsule and zona glomerulosa regions. Greater than 90% of the overall phosphodiesterase activity present in tissue extracts prepared from these regions was immunoprecipitated using a solid-phase monoclonal antibody reagent, indicating the cGS-PDE as the predominant phosphodiesterase isozyme. Immunohistochemical staining experiments of frozen thin sections of intact adrenal tissue revealed that the cGS-PDE present in this region was localized in the glomerulosa cells themselves. The role of this isozyme as a mediator of ANP-induced decreases in intracellular cAMP concentrations and aldosterone production was tested in primary cultures of bovine adrenal glomerulosa cells. In cells stimulated by ACTH, ANP treatment produced dose-dependent reductions in aldosterone secretion and cellular cAMP content over the same concentration range. Increases in aldosterone production elicited by three cell-permeable cAMP derivatives (8-bromo-cAMP, 8-p-chlorophenylthio-cAMP, and N6-2'-O-dibutyryl-cAMP) were antagonized by ANP, indicating a site of action distal to adenylate cyclase for this hormone. Because the relative magnitude of the ANP effect differed depending upon the derivative used, the three derivatives were compared with respect to their relative rates of in vitro hydrolysis by adrenal cGS-PDE. A positive correlation between their rates of hydrolysis and the degree to which the steroidogenic response produced by these derivatives was antagonized by ANP was demonstrated, further suggesting an ANP-induced activation of the cGS-PDE as being responsible for this effect. The possible contribution of an additional pathway mediated by an inhibitory guanine nucleotide binding regulatory protein (Gi) acting on adenylate cyclase was tested by pretreatment of primary glomerulosa cells with pertussis toxin. Levels of pertussis toxin sufficient to inhibit subsequent in vitro ribosylation did not significantly alter the ANP effect on aldosterone production, although a partial reduction in the ANP effect on cAMP levels was observed.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:High concentrations of a cGMP-stimulated phosphodiesterase mediate ANP-induced decreases in cAMP and steroidogenesis in adrenal glomerulosa cells. 184 62

The effects of CRH and somatostatin (SRIH) on adenylate cyclase (AC) activity, intracellular free calcium concentrations [( Ca2+]i) and in vitro ACTH release were investigated in six human ACTH-secreting pituitary adenomas. In all tumors, CRH induced a marked stimulation (from 69-210% at 10 nM), whereas SRIH caused a definite inhibition (from 29-50% at 100 nM) of membrane AC. When added together, CRH and SRIH caused a purely additive effect on AC. In adenomatous corticotrophs CRH (10 nM) caused [Ca2+]i to rise from 160 +/- 30 nM (mean +/- SD) to 410 +/- 95 nM. CRH-induced transients were biphasic, with an initial peak predominantly due to redistribution from intracellular Ca2+ stores and a secondary phase due to Ca2+ influx. The effects of CRH on [Ca2+]i were totally independent of the stimulation of AC. In fact, cAMP-elevating agents other than CRH did not modify [Ca2+]i. SRIH (100 nM) decreased resting [Ca2+]i (approximately 20-40%) as well as [Ca2+]i rises induced by CRH, arginine vasopressin, or high K+. The effect of SRIH on [Ca2+]i was maintained in presence of high cAMP levels, while was totally abolished after pertussis toxin pretreatment. CRH (10 nM) stimulated ACTH release (from 22.5 +/- 3.5 to 45.0 +/- 8.5 pmol/L) by an extent similar to that elicited by calcium ionophore and forskolin. By contrast, SRIH (0.1 microM) inhibited both basal and CRH-stimulated ACTH release. In conclusion, in human adenomatous corticotrophs SRIH exerts an inhibitory action by reducing both AC activity and, independently, [Ca2+]i. In this way, SRIH can efficiently counteract the stimulatory action of CRH that in these cells involves activation of both cAMP and Ca2+ pathways.
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PMID:Inhibition of basal and corticotropin-releasing hormone-stimulated adenylate cyclase activity and cytosolic Ca2+ levels by somatostatin in human corticotropin-secreting pituitary adenomas. 197 Aug 28

Recent data have shown that pretreatment of bovine adrenal fasciculata cells with insulin-like growth factor I (IGF-I) or insulin enhances the steroidogenic response to angiotensin II (A-II). In the present work we have studied the effects of both peptides on the first steps of the mechanism of action of A-II and on the amounts of pertussis toxin (PT)-sensitive guanine nucleotide binding proteins (Gi proteins). Both peptides increased A-II-induced phosphoinositide breakdown without modification of either A-II-induced Ca2+ uptake or the A-II-potentiating effect on ACTH-induced cAMP production. The effects of IGF-I at a nanomolar concentration were higher than those induced by insulin at a micromolar concentration, which in turn was higher than those induced by a nanomolar concentration of this peptide. Treatment of cells with pertussis toxin (0.5 microgram/ml) for 24 h reduced by 25% of the A-II-induced phosphoinositide breakdown in control cells and 32% and 28% in cells pretreated with insulin at nanomolar and micromolar concentrations, respectively, but had no significant effect in cells pretreated with IGF-I. No effect of pertussis toxin was observed on A-II-induced Ca2+ uptake or on its potentiating action on ACTH-induced cAMP production. Moreover, both IGF-I and insulin enhanced the amounts of Gi protein(s) evaluated by pertussis toxin ADP-ribosylation or immunoblotting. Again, the effects of insulin at nanomolar concentrations were lower than those induced by the same concentrations of IGF-I or insulin at micromolar concentrations. These results suggest that, in bovine adrenal fasciculata cells, A-II receptors are coupled to the phosphoinositide pathway through pertussis toxin sensitive and insensitive Gp protein(s). Moreover, the findings also indicate that the enhanced A-II responsiveness of IGF-I or insulin treated cells is in part mediated through an increase in the amount of G protein(s).
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PMID:Stimulatory effect of insulin and insulin-like growth factor I on Gi proteins and angiotensin-II-induced phosphoinositide breakdown in cultured bovine adrenal cells. 215 69

We studied the mechanism whereby insulin activates de novo phosphatidic acid synthesis in BC3H-1 myocytes. Insulin rapidly activated glycerol-3-phosphate acyltransferase (G3PAT) in intact and cell-free preparations of myocytes in a dose-related manner. The apparent Km of the enzyme was decreased by treatment with insulin, whereas the Vmax was unaffected. No activation was found by ACTH, insulin-like growth factor-I, angiotensin II, or phenylephrine, but epidermal growth factor, which, like insulin, is known to activate de novo phosphatidic acid synthesis in intact myocytes, also stimulated G3PAT activity. In homogenates or membrane fractions, the effect of insulin on G3PAT was fully mimicked by nonspecific or phosphatidylinositol (PI)-specific phospholipase C (PLC). An antiserum raised against PI-glycan-PLC completely blocked the effect of insulin on G3PAT. Although the above findings suggested involvement of a PLC in insulin-induced activation of G3PAT, neither diacylglycerol nor protein kinase C activation appeared to be involved. On the other hand, insulin stimulated the release of a cytosolic factor, which activated membrane-associated G3PAT. This cytosolic factor had a molecular weight of less than 5K as determined by Sephadex G-25 chromatography. NaF, a phosphatase inhibitor, blocked the activation of G3PAT by insulin, suggesting involvement of a phosphatase. Insulin-induced activation of G3PAT was also blocked by pretreatment of intact myocytes with pertussis toxin and by prior addition, to homogenates, of an antiserum that recognizes the C-terminal decapeptide of Gi alpha.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Insulin activates glycerol-3-phosphate acyltransferase (de novo phosphatidic acid synthesis) through a phospholipid-derived mediator. Apparent involvement of Gi alpha and activation of a phospholipase C. 217 32

Nitroimidazole derivatives dose-dependently decreased basal and CRF-stimulated ACTH release, basal and GRF-stimulated rat GH release, and basal rat PRL release in primary cultures of rat anterior pituitary cells. In addition, basal and CRF-stimulated mRNA coding for the ACTH precursor were reduced after preincubation with the nitroimidazole derivatives. Miconazole, econazole, isoconazole, clotrimazole, and bifonazole had similar or more pronounced effects on anterior pituitary function compared to ketoconazole, whereas metronidazole and etomidate were less effective. The positive correlation between the number of phenylated side-chains or phenolic rings of the imidazole molecule and the efficacy to inhibit activity on pituitary hormone secretion suggests a structure-activity relationship of these compounds. The effects of the nitroimidazole derivatives on anterior pituitary hormone release and biosynthesis were mediated by cAMP. Thus, basal and CRF-, cholera toxin-, and forskolin-stimulated adenylate cyclase activities in rat anterior pituitary cell membranes determined by cAMP formation were suppressed by the nitroimidazole derivatives. Pertussis toxin did not diminish the nitroimidazole derivative effect on cAMP formation. The adenylate cyclase inhibitory effect of these substances was independent of the presence of GTP in the assay system, underlining a direct effect on the catalytic subunit. In addition, basal and forskolin-stimulated cAMP generation in membranes of S49 lymphoma cyc-variants, which lack a functional Gs protein, was efficiently suppressed (by up to 90%) by the nitroimidazole derivatives. In conclusion, ketoconazole and other nitroimidazole derivatives inhibit anterior pituitary hormone synthesis and secretion apparently by a direct effect on the catalytic subunit of the adenylate cyclase system.
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PMID:Nitroimidazole derivatives inhibit anterior pituitary cell function apparently by a direct effect on the catalytic subunit of the adenylate cyclase holoenzyme. 254 44

The properties of the adenylate cyclase from forskolin-resistant mutants of Y1 adrenocortical tumor cells was compared with the properties of the enzyme from parental Y1 cells in order to localize the site of mutation. In parental Y1 cells, forskolin stimulated adenylate cyclase activity with kinetics suggestive of an interaction at two sites; in mutant cells, forskolin resistance was characterized by a decrease in enzymatic activity at both sites. Forskolin potentiated the enzyme's responses to NaF and guanyl-5'-yl imidodiphosphate (Gpp(NH)p) in parent and mutant clones, and the mutant enzyme showed the same requirements for Mg2+ and Mn2+ as did the parent enzyme. The adenylate cyclase associated with forskolin-resistant mutants was insensitive to ACTH and was less responsive to Gpp(NH)p than was the parent enzyme. In parental Y1 cells and in the forskolin-resistant mutants, cholera toxin catalyzed the transfer of [32P]ADP-ribose from [32P]NAD+ into three membrane proteins associated with the alpha subunit of Gs; however, the amount of labeled ADP-ribose incorporated into mutant membranes was reduced by as much as 70%. Both parent and mutant membranes were labeled by pertussis toxin to the same extent. The insensitivity of the mutant adenylate cyclase to ACTH and Gpp(NH)p and the selective resistance of the mutant membranes to cholera toxin-catalyzed ADP-ribosylation suggest that a specific defect associated with Gs is involved in the mutation to forskolin resistance in Y1 cells.
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PMID:Forskolin-resistant Y1 mutants harbor defects associated with the guanyl nucleotide-binding regulatory protein, Gs. 282 64


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