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)

Somatostatin (SRIF) is a potent inhibitor of angiotensin II (AII)-stimulated aldosterone production in rat adrenal glomerulosa cells. This inhibition can be prevented by pretreatment of the cells with pertussis toxin, but little else is known about either the specificity or the biochemical bases of SRIF action in this tissue. We therefore conducted detailed studies of the influence of SRIF on steroidogenesis elicited by AII and the other two physiological stimuli of aldosterone production, K+ and adrenocorticotropic hormone (ACTH), in rat adrenal glomerulosa cells. We also determined the effects of SRIF on cytosolic calcium concentration ([Ca2+]i) and cellular cAMP levels. In these studies, SRIF was found to inhibit the aldosterone responses elicited by low concentrations of all three stimuli, which are believed to promote steroid secretion via discrete but interacting cellular signalling mechanisms. In addition, SRIF consistently lowered cellular cAMP levels in the presence of each of the three agents. However, SRIF caused a small and transient increase rather than a decrease in basal ([Ca2+]i), and had no effect on the subsequent elevation of ([Ca2+]i) by AII and K+. These data indicate that activation of a Gi-like protein by SRIF influences steroid responses to all three major regulators of glomerulosa-cell function, and suggest that basal levels of cAMP play a facilitatory or permissive role in the control of aldosterone production by predominantly calcium-mobilizing regulators of mineralocorticoid secretion.
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PMID:Inhibitory actions of somatostatin on cyclic AMP and aldosterone production in agonist-stimulated adrenal glomerulosa cells. 248 36

The plasma-membrane receptors, coupling mechanisms, and effector enzymes that mediate target-cell activation by angiotensin II (AII) have been characterized in rat and bovine adrenal glomerulosa cells. The AII holoreceptor is a glycoprotein of Mr approximately 125,000 under non-denaturing conditions. Photoaffinity labeling of AII receptors with azido-AII derivatives has shown size heterogeneity among the AII binding sites between species and target tissues, with Mr values of 55,000 to 79,000. Such variations in molecular size probably reflect differences in carbohydrate content of the individual receptor sites. The adrenal AII receptor, like that in other tissues, is coupled to the inhibitory guanine nucleotide inhibitory protein (Ni). However, studies with pertussis toxin have shown that stimulation of aldosterone production by AII is not mediated by Ni but by a pertussis-insensitive nucleotide regulatory protein of unidentified nature. Although Ni is not involved in the stimulatory action of AII on steroidogenesis, it does mediate the inhibitory effects of high concentrations of AII upon aldosterone production. The actions of AII on adrenal cortical function are thus regulated by at least two guanine nucleotide regulatory proteins that are selectively activated by increasing AII concentrations. The principal effector enzyme in AII action is phospholipase C, which is rapidly stimulated in rat and bovine glomerulosa after AII receptor activation. AII-induced breakdown of phosphatidylinositol bisphosphate (PIP2) and phosphatidylinositol phosphate (PIP) leads to formation of inositol 1,4,5-trisphosphate (IP3) and inositol 1,4-bisphosphate (IP2). These are metabolized predominantly to inositol-4-monophosphate, which serves as a marker of polyphosphoinositide breakdown, whereas inositol-1-phosphate is largely derived from phosphatidylinositol hydrolysis. The AII-stimulated glomerulosa cell also produces inositol 1,3,4-trisphosphate, a biologically inactive IP3 isomer formed from Ins-1,4,5-trisphosphate via inositol tetrakisphosphate (IP4) during ligand activation in several calcium-dependent target cells. The Ins-1,4,5-P3 formed during AII action binds with high affinity to specific intracellular receptors that have been characterized in the bovine adrenal gland and other AII target tissues, and may represent the sites through which IP3 causes calcium mobilization during the initiation of cellular responses.
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PMID:Angiotensin II receptors and mechanisms of action in adrenal glomerulosa cells. 282 11

Using freshly isolated bovine adrenal glomerulosa cells we examined the inhibitory effect of atrial natriuretic peptide (ANP) on aldosterone secretion stimulated by agonists that use either the Ca2+-phosphoinositide or cAMP messenger system. In a continuous perifusion system, angiotensin II (AII) induces a prompt initial rise in aldosterone secretion, followed by a sustained secretory response. Both phases of secretion are rapidly and independently inhibited by ANP. The role of two cyclic nucleotides, cGMP and cAMP, as mediators of this ANP-induced inhibition was examined. The effect of 8-bromo-cGMP (1-100 microM) or (Bu)2cGMP (1-50 microM) on the AII-stimulated rate of secretion was studied in a perifusion system. Either analog, whether added early or late, maximally inhibited by 20-30% only the late or sustained phase of aldosterone secretion. The effect of ANP on cellular cAMP content was examined in a static incubation system. Although ANP caused a reduction in the cAMP content of cells stimulated with either AII or ACTH, it had little or no effect on the cAMP levels in cells stimulated with carbachol. In AII- and ACTH-stimulated cells, the relationship between reduced cAMP content and reduced secretion was explored. In the AII-stimulated cell inhibited by ANP, simple restoration of cAMP content with forskolin did not restore the secretory rate. Pertussis toxin treatment blocked the inhibitory effect of ANP on cAMP content, but did not block its inhibition of secretion. In the ACTH-stimulated cell, reversal of the ANP-induced reduction of cAMP with forskolin, partially restored the stimulated rate of secretion, although restoration of cAMP with a 10-fold higher dose of ACTH did not restore the stimulated rate of secretion in the presence of ANP. These results imply that both the ANP-induced rise in cGMP and the ANP-induced decrease in cellular cAMP content may contribute to the inhibition of steroidogenesis. However, these inhibitory messages do not induce either the magnitude or the temporal pattern of inhibition induced by ANP. Thus, in the adrenal multiple messenger systems may underlie the action of ANP.
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PMID:The role of cyclic nucleotides in atrial natriuretic peptide-mediated inhibition of aldosterone secretion. 283 96

The involvement of guanine nucleotide regulatory proteins in the steroidogenic response of the adrenal glomerulosa to angiotensin II (AII) was investigated by analyzing the effects of Bordetella pertussis toxin (PT) on several aspects of AII action. These included receptor binding, stimulation of aldosterone production and GTPase activity, inhibition of cAMP production, and attenuation of the aldosterone response at high angiotensin concentrations. Pretreatment of glomerulosa cells with PT abolished the inhibitory effects of both AII and somatostatin (SRIF) on ACTH-stimulated cAMP production. Under the same incubation conditions, the stimulation of aldosterone secretion by submaximal and maximal steroidogenic concentrations of AII was completely unaffected by the toxin. However, the attenuation of steroid responses seen with supramaximal concentrations of AII was abolished. In addition, the ability of SRIF to inhibit AII-stimulated steroid production was markedly reduced by PT treatment. The binding of [125I]AII to high affinity sites in intact cells and particulate fractions, and modulation of the binding by guanine nucleotides, were unaffected by toxin pretreatment, even under conditions where a 40-41K protein was completely ADP ribosylated. In contrast, the toxin substantially diminished the binding of [125I]Tyr0-SRIF to SRIF receptors in glomerulosa cells (by 50% after 5 h and by 90% after 20 h). These results indicate that Ni or a similar protein probably mediates the inhibition of cAMP formation by AII and the attenuation of the steroid response by high concentrations of AII as well as the inhibitory actions of SRIF in the adrenal glomerulosa cell. Furthermore, the lack of effect of PT on AII binding and stimulation of GTPase activity suggests the existence of an additional pertussis-insensitive guanine nucleotide-regulatory protein that is activated by lower concentrations of AII and mediates the stimulation of aldosterone production.
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PMID:Control of aldosterone production by angiotensin II is mediated by two guanine nucleotide regulatory proteins. 288 77

The effect of glucocorticoid on the prostaglandin E1 (PGE1)-mediated cyclic AMP (cAMP) formation by vascular smooth muscle cells (VSMC) from renal arteries (RA) was studied in rats. Dexamethasone (DEX) at concentrations ranging from 10(-10) to approximately 10(-8) mol/l dose-dependently potentiates the PGE1-mediated response. This facilitation began at 6 h and reached its maximum after 24 h of DEX administration. Aldosterone (10(-6) mol/l) did not affect the dose-response curve of PGE1. Inhibitors of protein and RNA synthesis blocked this glucocorticoid effect. The basal activity of adenylate cyclase in DEX-treated cells was twice as high as in control cells. Treatment of VSMC with DEX increased cholera toxin- and pertussis toxin-stimulated adenylate cyclase activity. DEX treatment also augments forskolin-stimulated adenylate cyclase activity. These results suggest that DEX increases PGE1-mediated cAMP formation of VSMC from RA through a mechanism that involves the induction of protein synthesis, and that the activation of the catalytic unit may play some role in this facilitating process.
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PMID:Effect of glucocorticoid on prostaglandin E1 mediated cyclic AMP formation by vascular smooth muscle cells. 290 77

Angiotensin II (AII) receptors in adrenal glomerulosa cells are coupled to adenylate cyclase inhibition. We investigated the importance of cyclase inhibition in adrenal steroidogenesis by treating adrenal glomerulosa cells with the toxin of Bordetella pertussis (20 ng/ml) for 3 and 18 h. This treatment prevented inhibition of forskolin-stimulated adenylate cyclase by AII. However, the aldosterone response to AII was not altered by toxin treatment. These results strongly suggest that adenylate cyclase inhibition is not directly involved in mediating the adrenal actions of AII. In addition, ACTH-induced steroidogenesis also was unaffected by toxin treatment demonstrating that cyclase inhibition is not involved in suppressing steroidogenesis via the cAMP pathway.
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PMID:Adenylate cyclase inhibition is not involved in the adrenal steroidogenic response to angiotensin II. 301 40

1. The receptor-activated mechanisms that mediate the steroidogenic actions of angiotensin II (AII) have been characterized in rat and bovine adrenal glomerulosa cells. In rat adrenal cells, the AII receptor is coupled to a guanine nucleotide inhibitory protein which reduces adenylate cyclase activity and cyclic AMP production. However, receptor-mediated stimulation of aldosterone production by AII is exerted through a separate pertussis-insensitive nucleotide regulatory protein that subserves coupling of activated receptors to phospholipase C. 2. In AII-stimulated glomerulosa cells, hydrolysis of phosphatidylinositol (4,5)-bisphosphate (PIP2) by phospholipase C yields diacylglycerol and inositol 1,4,5-trisphosphate (Ins-P3), which act as second messengers by activating calcium-calmodulin and calcium-phospholipid dependent protein kinase pathways. Ins-1,4,5-P3 is a potent stimulus of intracellular calcium mobilization, and is promptly inactivated by two major routes of metabolism. Direct degradation of Ins-1,4,5-P3 by a 5-phosphatase gives inositol 1,4-bisphosphate which in turn is metabolized to inositol-4-monophosphate. The latter product can be derived only from higher inositol phosphates, and thus serves as a specific marker of polyphosphoinositide breakdown in agonist-stimulated cells. In contrast, inositol-1-phosphate is largely derived from phosphatidylinositol hydrolysis, which is not increased during the initial phase of AII action. 3. Ins-1,4,5-P3 formed in AII-stimulated glomerulosa cells is also phosphorylated by a calcium-calmodulin dependent 3-kinase to form inositol 1,3,4,5-tetrakisphosphate (Ins-P4), which is rapidly dephosphorylated to the biologically inactive Ins-1,4,5-P3 isomer, Ins-1,3,4-trisphosphate. The latter metabolite, like Ins-1,4,5-P3, is both degraded to lower phosphates (Ins-3,4,P2 and Ins-1,3-P2) and phosphorylated to form a new tetrakisphosphate isomer (Ins-1,3,4,6-P4). Ins-1,4,5-P3 formed during AII action is bound with high affinity to specific intracellular receptors through which InsP3 causes calcium mobilization during the initiation of cellular responses to AII and other calcium-dependent ligands.
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PMID:Control of glomerulosa cell function by angiotensin II: transduction by G-proteins and inositol polyphosphates. 315 62

Studies in extrarenal, nonepithelial cells such as human lymphocytes and smooth muscle cells indicate that aldosterone produces not only delayed genomic effects, but also rapid, non-genomic effects on transmembrane electrolyte movements. These non-genomic events involve the immediate activation of the sodium/proton-exchanger of the cell membrane at very low, physiological concentrations of aldosterone in both lymphocytes and cultured rat vascular smooth muscle cells. This new pathway for mineralocorticoid action is further characterized by a 10,000-fold selectivity for aldosterone over cortisol and the ineffectiveness of spironolactones, classical mineralocorticoid antagonists, as antagonists of the response. Aldosterone-specific binding sites have been demonstrated in the plasma membrane of human lymphocytes, with features identical to those seen for the rapid aldosterone effects in the same cells. As second messenger the inositol-1,4,5-trisphosphate pathway has been identified both in human lymphocytes and vascular smooth muscle cells, which respond over the same rapid time course. In addition, the aldosterone effect on inositol-1,4,5-trisphosphate production in vascular smooth muscle cells is sensitive to pertussis toxin, but not to cholera toxin, pointing to a possible involvement of G-proteins in the cellular signalling. This article reviews the data supporting a new, two-step model for successive non-genomic and genomic mineralocorticoid effects.
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PMID:Nongenomic aldosterone effects: the cell membrane as a specific target of mineralocorticoid action. 779 3

Specific hydrolysis of GTP catalyzed by membranes prepared from A6 epithelial cells grown on porous supports was measured. Aldosterone treatment of the cells for 4 h increased Na+ transport and stimulated GTP hydrolysis by apical membranes in vitro more than twofold over basal levels. This stimulation was attributed to an increase in maximum velocity with little change in Michaelis-Menten constant values. Na+ transport rate and GTP hydrolysis were linearly correlated after aldosterone. This relationship was maintained when aldosterone's response was blunted by various inhibitors. Spironolactone decreased both the hormone-stimulated guanosinetriphosphatase (GTPase) and the Na+ transport rate. Pertussis toxin, which exerted minimal effects on basal rates, reduced the increase of Na+ current normally observed after aldosterone and the hormone stimulation of GTPase activity. The expression of classical Gi/Go-type G proteins was not increased after hormone treatment. When A6 cells were grown on nonporous plastic dishes, aldosterone neither stimulated GTPase activity nor increased amiloride-blockable 22Na+ fluxes. We propose that activation of one or more G proteins in the apical membrane of A6 cells is directly involved in the natriferic action of aldosterone.
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PMID:Aldosterone stimulation of GTP hydrolysis in membranes from renal epithelia. 790 Jul 64

Corticosteroid regulation of Na/K-ATPase is of key importance in the modulation of Na+ transport across renal tubular epithelia. In amphibian renal cells, aldosterone induction of Na/K-ATPase alpha 1 and beta 1 subunit gene transcription is mediated by an indirect mechanism dependent on the synthesis of a labile protein. In mammalian target cells, while both mineralo- and glucocorticoids increase the levels of Na/K-ATPase alpha 1 and beta 1 subunit mRNA and enzyme activity, they are diminished by glycyrrhetinic acid (GE), the active ingredient of licorice. To investigate the mechanisms underlying the regulation of mammalian renal Na/K-ATPase, levels of alpha 1 and beta 1 mRNA were measured in rat kidney epithelial (NRK-52E) cells treated with a range of concentrations of aldosterone, corticosterone and GE in the presence of a specific inhibitor of mRNA synthesis, dichlororibofuranosylbenzimidazole (DRB), an inhibitor of total RNA synthesis, actinomycin D (ActD), and the protein synthesis inhibitor cycloheximide (CHX). In addition, GE was co-incubated with the sodium channel antagonist benzamiloride (BZ). The increase in both alpha 1 and beta 1 mRNA levels following aldosterone and corticosterone was completely abolished by treatment with ActD and DRB, while CHX did not affect this response. Similarly, the GE-induced decrease in alpha 1 and beta 1 mRNA was also completely abolished by ActD and DRB, but not by CHX or by BZ. The half-lives of alpha 1 and beta 1 mRNA in these cells (means +/- S.E.M., n = 4), estimated from the rate of mRNA decay in the presence of DRB, were 6.8 +/- 0.3 and 4.8 +/- 0.2 h respectively. This was unaffected by GE. The inhibitory action of GE on alpha 1 and beta 1 mRNA levels was accompanied by a dose-dependent decrease in levels of intracellular cAMP (means +/- S.E.M., n = 4) from 395 +/- 28 fmol cAMP/microgram total cell protein to between 275 +/- 19 fmol/micrograms total cell protein (0.1 microM GE) and 78 +/- 11 fmol/micrograms total cell protein (10 microM GE). This was abolished following down-regulation of protein kinase C by prolonged treatment with the phorbol ester tetradecanoylphorbol-13-acetate (TPA), and by pertussis toxin (PT), but not by cholera toxin (CT). Indeed, subunit mRNA levels were increased by 8-bromo-cAMP (2.2-fold) and stimulators of adenylate cyclase activity, i.e. forskolin (2.1-fold), PT (2.1-fold) and CT (1.9-fold), but not by TPA.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Transcriptional regulation of Na/K-ATPase by corticosteroids, glycyrrhetinic acid and second messenger pathways in rat kidney epithelial cells. 854 17


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