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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The identity of phosphoinositol isomers accumulating on stimulation of primary cultures of bovine adrenocortical zona fasciculata/reticularis cells with angiotensin II (AII), in the presence of Li+, has been established by chromatographic separation on a MonoQ HR5/5 column. The metabolism of inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) in a broken cell preparation has also been studied in the absence or presence of added ATP. Our results show that Ins(1,4,5)P3 is formed within 5 s of stimulation of whole cells, but is rapidly converted to Ins(1,3,4)P3 through an Ins(1,3,4,5)P4 intermediate. All the phosphoinositol products accumulating on prolonged (15 min) stimulation of whole cells (Ins1P, Ins4P, Ins(1,3)P2, Ins(1,4)P2, Ins(1,3,4)P3, Ins(1,4,5)P3, Ins(1,3,4,5)P4) can be accounted for by the metabolism of Ins(1,4,5)P3 in broken cells, either through direct dephosphorylation in the absence of added ATP (Ins(1,4)P2, Ins4P) or through dephosphorylation of Ins(1,3,4,5)P4 formed in the presence of added ATP (Ins(1,3,4)P3, Ins(1,3)P2 and Ins1P). Our results provide further evidence to suggest that AII stimulates the rapid and sustained breakdown of phosphatidylinositol 4,5-diphosphate (PtdIns(4,5)P2) to form Ins(1,4,5)P3.
Mol Cell Endocrinol 1992 Jan
PMID:Identification and metabolism of phosphoinositol species formed on angiotensin II stimulation of zona fasciculata-reticularis cells from the bovine adrenal cortex. 155 69

The pharmacological effects of angiotensin II (AII) are potently inhibited by several peptide and recently synthesized nonpeptide AII receptor antagonists. The interaction of sarcosine1, isoleucine8-AII (sarile), sarcosine1,O-methyltyrosine4-AII (sarmesin), and the nonpeptide AII antagonists 2-n-butyl-4-chloro-5- hydroxymethyl-1-[(2'-(1H-tetrazole-5-yl)biphenyl-4-yl)- methyl]imidazole (DuP 753, Losartan potassium) and its metabolite 2-n-butyl-4-chloro-1-[(2'-(1H-tetrazole-5-yl)biphenyl-4-yl)methyl]imidaz ole - 5-carboxylic acid (EXP3174) with AII binding sites was investigated in radioligand binding and functional studies. Sarile, sarmesin, DuP 753, and EXP3174 inhibited 125I-AII binding to rat lung tissue, with Ki values of 3.5, 16.1, 23.7, and 10.4 nM, respectively. The Hill coefficients of all displacement curves, except for sarile (nH, 1.45), were not significantly different from unity. In functional experiments using rabbit aorta, sarmesin and DuP 753 competitively inhibited the contractile response to AII, with pA2 values of 6.75 and 8.01, respectively. Sarile, in contrast, revealed noncompetitive antagonism, i.e., the maximum contractile force and the slope of the concentration-contractile force curve were significantly and concentration-dependently depressed. The concentration-contractile response curve for AII was shifted to the right in a parallel fashion in the presence of EXP3174 (3 nM to 1 microM); however, the maximum contractile force was significantly decreased, by 24%. The marked noncompetitive antagonism of sarile (3 nM) was reversed in the presence of increasing concentrations of sarmesin (30 nM to 30 microM) or DuP 753 (10 nM to 1 microM), whereas in the presence of increasing concentrations of EXP3174 (3-300 nM) a 25% depression in maximum contractile force persisted. Moreover, the reduction of the maximum contractile force by EXP3174 (10 nM) was concentration-dependently restored in the presence of increasing concentrations of DuP 753 (10 nM to 1 microM), indicating interaction with the same binding site. Whereas sarile (0.3-10 nM) did not affect the 125I-AII binding capacity in radioligand saturation experiments, a 54% reduction of Bmax was observed in the presence of 100 nM EXP3174. The data provide evidence that all antagonists inhibit the functional response to AII by interacting with a common binding site at the receptor. The noncompetitive behavior of sarile seems to be due to slow dissociation from this receptor site. An additional mechanism must be postulated for EXP3174. An allosteric interaction with the receptor, as suggested by the reduction in Bmax, may be, at least in part, responsible for the nonclassical antagonism of this compound.
Mol Pharmacol 1992 Jun
PMID:Different types of receptor interaction of peptide and nonpeptide angiotensin II antagonists revealed by receptor binding and functional studies. 161 10

Endothelin (ET) receptors are present in pituitary cells and stimulate hormone release through the phosphoinositide/Ca2+ signaling system. In pituitary cell suspensions, ET caused [Ca2+]i elevations of much higher amplitudes than those induced by other vasoactive hormones, including angiotensin II, vasopressin, and noradrenalin. The action of ET was coupled to rapid and transient activation of exocytosis in gonadotrophs, thyrotrophs, somatotrophs, and lactotrophs. In contrast, angiotensin II did not stimulate luteinizing hormone release, and luteinizing hormone responses to vasopressin and noradrenalin were very small. Single gonadotrophs exhibited three types of [Ca2+]i responses to increasing doses of ET, (a) subthreshold responses, with amplitude modulation; (b) threshold-oscillatory responses, with frequency modulation; and (c) threshold-biphasic responses, as the summation of single Ca2+ spikes. The same [Ca2+]i patterns were also seen in gonadotropin-releasing hormone (GnRH)-stimulated cells. In the presence of [Ca2+]e, the amplitudes of the Ca2+ spikes progressively decreased during continuous stimulation with ET or GnRH, reaching the nonoscillatory plateau level after 200-400 sec of stimulation. In cells stimulated with GnRH, subsequent exposure to ET, GnRH, or ionomycin during the plateau phase did not elicit further increases in [Ca2+]i, whereas cells stimulated with ET responded partially to all three agents. In addition, cells exposed to ET or GnRH for 30 min, followed by a 30-min recovery period, were able to mount a full [Ca2+]i response to GnRH, but not to ET-1. Similarly, both peptides elicited rapid increases in LH release, with comparable potencies, but the response to ET decreased much more rapidly during sustained stimulation and gonadotrophs became refractory to further ET stimulation. This is in part attributable to rapid endocytosis of ET receptors during continuous agonist stimulation. These data indicate that ET exerts potent but transient secretory actions in several pituitary cell types and is a potential regulator of gonadotropin release. The initial receptor-coupling events in both ET- and GnRH-stimulated cells are similar, but the differences observed during continuous or repetitive stimulation indicate that the ET receptor pathway undergoes rapid desensitization that is critical in determining the distinct cellular responses to the two peptides.
Mol Pharmacol 1991 Jun
PMID:Calcium signaling and secretory responses in endothelin-stimulated anterior pituitary cells. 164 50

The inward chloride current induced by angiotensin II (AII) in Xenopus oocytes shows strong and homologous desensitization, and was suggested to be mediated by phosphatidylinositol (PI) hydrolysis (Sakuta et al., 1991, Eur. J. Pharmacol. Mol. Pharmacol. 208, 31). As a model of agonist-induced desensitization of receptors coupled with PI hydrolysis, the mechanism of the desensitization of endogenous AII receptors in oocytes was investigated. Incubation of collagenase-treated oocytes with staurosporine significantly augmented the peak amplitude of AII responses, prolonged their duration, and increased the ratio of oocytes responsive to AII. Moreover, staurosporine-pretreatment made oocytes be consistently responsive to every application of AII. These effects of staurosporine were inhibited by incubation of staurosporine-treated oocytes with 12-O-tetradecanoylphorbol 13-acetate (TPA) but not with dibutyryl cAMP. TPA also attenuated AII responses in staurosporine-untreated control oocytes. These results suggest that staurosporine suppresses the desensitization of endogenous AII receptors in oocytes by blocking protein kinase C (PKC), and the desensitization is likely to be due to phosphorylation by PKC of the receptors or the molecules comprising an AII receptor complex.
 ...
PMID:Desensitization of endogenous angiotensin II receptors in Xenopus oocytes: a role of protein kinase C. 165 20

Endothelin-1 (ET-1) is a potent, vasoconstrictive peptide isolated from culture media of vascular endothelial cells. The binding of ET-1 to membrane preparations from rat and bovine lung was studied using radioiodinated ET-1 (125I-ET-1). With both membrane preparations, 125I-ET-1 showed saturable binding to a single class of high affinity sites. Scatchard analysis of the binding data gave dissociation constants (Kd) for ET-1 of 0.22 nM and 0.15 nM, and receptor densities (Bmax) of 6.1 pmol/mg and 2.7 pmol/mg for rat and bovine lung membranes, respectively. Photo-reactive radioiodinated ET-1, N epsilon 9-azidobenzoyl-125I-ET-1, was synthesized and purified as a mono-reactive affinity labeling reagent. This reagent was used for affinity labeling of ET-1 receptor in bovine and rat lung membranes. Photoaffinity labeling followed by sodium dodecyl sulfate gel electrophoresis and autoradiography gave a radiolabeled protein band with an apparent Mr of 34,000 in both membrane preparations. The labeling of this protein band was inhibited by cold ET-1 in a concentration-dependent manner. Labeling was not abolished by unrelated peptides such as angiotensin II and [Arg8]-vasopressin, or by structurally related bee venom apamin. These results indicate that the ET-1 receptor or its ligand binding subunit consists of a 34,000 Da polypeptide.
Mol Cell Endocrinol 1991 Aug
PMID:Affinity labeling of endothelin receptors in bovine and rat lung membranes by N epsilon 9-azidobenzoyl-125I-endothelin-1. 165 62

The regulated expression of the genes encoding the various steroidogenic enzymes is a crucial component in the control of steroid hormone biosynthesis. Tissue-specific transcription of each of the steroidogenic enzyme genes determines the array of enzymes present within a steroidogenic tissue, and therefore the types of steroid hormones the tissue produces. Transcriptional regulation also determines developmental changes in the steroid hormones synthesized by steroidogenic tissues and for the quantitative regulation of steroid hormones necessary for reproduction and for maintaining physiological homeostasis. The molecular mechanisms governing transcriptional regulation of steroidogenic enzyme genes is now being studied. The results so far indicate that, like most other genes, transcription of steroidogenic enzyme genes is regulated by cis-elements in the 5' flanking DNA of the genes that bind trans-acting proteins found in the nucleus. Several types of cis-elements have been identified: elements responsible for basal transcription, for induction by cAMP, and for both basal and cAMP induction. Some of the basal cis-elements identified may have a role in tissue-specific transcription of certain steroidogenic enzyme genes in steroidogenic tissues. We have also identified regions in both the human P450scc and human P450c17 promoters that repress transcription when activated by the Ca2+/protein kinase C intracellular second messenger system used by angiotensin II. This review summarizes our current understanding of transcriptional regulation of the steroidogenic enzyme genes.
J Steroid Biochem Mol Biol 1991
PMID:The role of transcriptional regulation in steroid hormone biosynthesis. 165 86

Long-term regulation of mammalian steroid hormone synthesis occurs principally by transcriptional regulation of the gene for the rate-limiting cholesterol side-chain cleavage enzyme P450scc. Adrenal steroidogenesis is regulated primarily by two hormones: adrenocorticotropin, which works via cyclic AMP (cAMP) and protein kinase A, and angiotensin II, which works via Ca2+ and protein kinase C. Forskolin and 8-bromo-cAMP stimulated, while prolonged treatment with a phorbol ester (12-O-tetradecanoylphorbol-13-acetate [TPA]) and a calcium ionophore (A23187) additively suppressed accumulation of endogenous P450scc mRNA in transformed murine adrenal Y1 cells. In Y1 cells transfected with 2,327 base pairs of the human P450scc promoter fused to the bacterial gene for chloramphenicol acetyltransferase (CAT), forskolin increased CAT activity 900% while combined TPA plus A23187 reduced CAT activity to 15% of the control level. Forskolin induced the P450scc promoter as rapidly as a promoter containing two cAMP-responsive elements fused to a simian virus 40 promoter, a system known to respond directly to cAMP. Basal expression was increased by sequences between -89 and -152 and was increased further by sequences between -605 and -2327. This upstream region also conferred inducibility by cAMP. TPA plus A23187 transiently increased CAT activity before repressing it, reflecting the complex actions of angiotensin II in vivo. Repression by prolonged treatment with TPA plus A23187 was mediated by multiple elements between -89 and -343. Induction of CAT activity by forskolin was not diminished by treatment with TPA plus A23187, nor were the regions of the promoter responsible for regulation by the two pathways coisolated. Thus, the human gene for P450scc is repressed by TPA plus A23187 by mechanisms and sequences independent of those that mediate induction by cAMP.
Mol Cell Biol 1990 Nov
PMID:Human P450scc gene transcription is induced by cyclic AMP and repressed by 12-O-tetradecanoylphorbol-13-acetate and A23187 through independent cis elements. 170 Feb 77

Cellular responses to epidermal growth factor (EGF) are dependent on the tyrosine-specific protein kinase activity of the cell-surface EGF receptor. Previous studies using WB rat liver epithelial cells have detected at least 10 proteins whose phosphotyrosine (P-Tyr) content is increased by EGF. In this study, we have examined alternate modes of activating tyrosine phosphorylation. Treatment of WB cells with hormones linked to Ca2+ mobilization and protein kinase C (PKC) activation, including angiotensin II, [Arg8]vasopressin, or epinephrine, stimulated rapid (less than or equal to 15-s) and transient increases in the P-Tyr content of several proteins (p120/125, p75/78, and p66). These proteins, detected by anti-P-Tyr immunoblotting, were similar in molecular weight to a subset of EGF-sensitive P-Tyr-containing proteins (P-Tyr-proteins). The increased P-Tyr content was confirmed by [32P]phosphoamino acid analysis of proteins recovered by anti-P-Tyr immunoprecipitation. Elevating intracellular [Ca2+] with the ionophore A23187 or ionomycin or with the tumor promoter thapsigargin mimicked the effects of hormones on tyrosine phosphorylation, whereas treatment with a PKC-activating phorbol ester did not. In addition, responses to angiotensin II were not diminished in PKC-depleted cells. Ca2+ mobilization, measured by fura-2 fluorescence, was coincident with the increase in tyrosine phosphorylation in response to angiotensin II or thapsigargin. Loading cells with the intracellular Ca2+ chelator bis-(o-aminophenoxy)ethane-N ,N ,N' , N'-tetraacetic acid (BAPTA) inhibited the appearance of all P-Tyr-proteins in response to angiotensin II, thapsigargin, or ionophores, as well as two EGF-stimulated P-Tyr-proteins. The majority of EGF-stimulated P-Tyr-proteins were not affected by BAPTA. These studies indicate that angiotensin II can alter protein-tyrosine phosphorylation in a manner that is secondary to, and apparently dependent on, Ca2+ mobilization. Thus, ligands such as EGF and angiotensin II, which act through distinct types of receptors, may activate secondary pathways involving tyrosine phosphorylation. These results also raise the possibility that certain growth-promoting effects of Ca2+ -mobilizing agents such as angiotensin II may be mediated via tyrosine phosphorylation.
Mol Cell Biol 1990 Dec
PMID:Angiotensin II stimulates protein-tyrosine phosphorylation in a calcium-dependent manner. 170 Oct 16

The present studies were performed using primary monolayer cultures of bovine glomerulosa cells to determine whether the elevation in cytosolic calcium concentration produced by angiotensin II was accompanied by an elevation in mitochondrial calcium. Exchangeable mitochondria calcium content was assessed indirectly by measuring the changes in cytosolic calcium concentration and calcium efflux produced by the mitochondrial uncoupler, carbonyl cyanide m-chlorophenylhydrazone (CCCP). Total mitochondrial calcium content was also assessed directly by atomic absorption spectroscopy. CCCP had a direct effect to promote calcium release from an oligomycin/antimycin-sensitive (mitochondrial) calcium pool in permeabilized cells. In intact cells, CCCP caused rapid reductions in cellular ATP content and the ratio of ATP to ADP. Still, its effects on calcium dynamics were exerted primarily at the mitochondrial level as evidenced by inhibition with ruthenium red, but not dantrolene. As expected, angiotensin II produced a rapid increase in calcium efflux and an equally rapid and sustained increase in cytosolic calcium concentration. Nonetheless, CCCP-stimulated elevations in cytosolic calcium concentration and calcium efflux were reduced by angiotensin II in a concentration-dependent manner. Total mitochondrial calcium content was also lower in angiotensin-treated than in control cells. These results indicate that angiotensin II causes a net decrease in mitochondrial calcium stores. On the basis of these data, it is proposed that alterations in calcium metabolism initiated by angiotensin II are exerted not only at the membrane and cytosolic levels but also at the level of the mitochondria. Changes in mitochondrial calcium dynamics may directly contribute to the regulation of mitochondrial steroidogenic enzymes by angiotensin II.
Mol Cell Endocrinol 1990 Dec 03
PMID:Evidence that angiotensin II decreases mitochondrial calcium in the glomerulosa cell. 170 33

Angiotensin II has previously been reported to have in vivo and in vitro cardiac hypertrophic effects. We used the salt-sensitive Dahl rat genetic strain to separate mechanical (pressure overload) vs. hormonal (renin-angiotensin system) input in cardiac hypertrophy. Blood pressure was significantly increased and left ventricular hypertrophy, as indexed by LV/BW ratios, was present at 7 and 15 days in rats receiving 4% and 8% NaCl compared to the 1% controls. There was no effect of the angiotensin converting enzyme inhibitor, enalapril maleate, on lowering the blood pressure in 8% NaCl-treated animals, however, there was a significant reduction in LV/BW ratio in 8% NaCl-treated animals that received this drug. Left ventricular angiotensinogen mRNA activity was significantly reduced in rats receiving 4% and 8% NaCl. In this model of hypertension the cardiac hypertrophy which develops is largely dependent on mechanical forces though there remains a significant contribution to this process from either circulating or localized angiotensin II production. Regulation of angiotensinogen gene expression in the hypertrophied left ventricle suggests that volume and electrolyte control of angiotensinogen gene expression in the heart and/or hereditary factors are predominant in the control of regulation of this gene in the left ventricle of Dahl rats.
Mol Cell Biochem
PMID:Angiotensin converting enzyme inhibition in Dahl salt-sensitive rats. 171 20


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