Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this article, current knowledge about the mechanism of action of ACTH will be reviewed. Emphasis will be placed on events which occur subsequent to binding of ACTH to its receptor, stimulation of adenylate cyclase, and activation of protein kinase. In the first part of the review, the acute action of ACTH will be discussed with emphasis on present hypotheses as to the roles of calcium, phospholipids, sterol carrier proteins, and a "labile protein" activator of cholesterol side-chain cleavage. The presumptive role of these factors to increase the binding of cholesterol to the mitochondrial cholesterol side-chain cleavage enzyme will be discussed in the light of the concept that such binding is the step in steroidogenesis which is activated during the acute response of the adrenal cell to ACTH. In the second part of the article, the long-term action of ACTH to increase the levels of steroidogenic enzymes will be reviewed. Recent evidence is indicative that ACTH causes induction of the synthesis of key steroidogenic enzymes present in both the mitochondria and the microsomes. This appears to result from transcription of genes specific for these various species of cytochrome P-450 and ancillary proteins, resulting in increased synthesis of specific forms of mRNA. Whereas the mitochondrial steroidogenic enzymes are synthesized on cytoplasmic polysomes as precursor forms of higher molecular weight, the microsomal proteins are synthesized as forms of similar molecular weight to the mature forms.
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PMID:Regulation by ACTH of steroid hormone biosynthesis in the adrenal cortex. 631 63

The control of androgen production by the Leydig cell is dependent upon the episodic secretion of hormone (LH), which is released from the anterior pituitary gland in pulses of high biological activity. This mode of episodic LH secretion supports steroidogenic enzyme activity in the testis through interaction with LH receptors and stimulation of the adenylate cyclase/protein kinase sequence, leading to phosphorylation of key intermediates in the steroid biosynthetic pathway. The plasma membrane events that are rapidly activated by the specific interaction of LH or hCG with Leydig cell receptors include increased binding of guanyl nucleotide, and stimulation of cAMP-independent, Ca2+-dependent phosphorylation of a 44,500 Mr protein, with the characteristics of the adenylate cyclase nucleotide regulatory unit. Hormonal activation of adenylate cyclase is affected by Ca2+ with the same concentration-dependence, suggesting that nucleotide-induced phosphorylation is related to activation of the catalytic cyclase unit. In addition to the characteristic increases in pregnenolone synthesis and androgen production, gonadotropin-stimulated Leydig cells show prominent changes in LH receptor content and steroidogenic activity that modify their subsequent responses to hormonal signals. Thus, after exposure to increased LH and hCG levels in vivo and in vitro, LH receptors show an initial transient increase (up-regulation) followed by a marked decrease (down-regulation) and a prolonged depletion of LH receptor sites. Large doses of hCG cause "early" (prior to pregnenolone) and "late" steroidogenic lesions (17 alpha-hydroxylase, 17-20 desmolase) that are independent of receptor loss. The early lesion is partly due to reduced activity of HMG CoA reductase, and is mainly attributable to the increased activity of an inhibitory protein factor that modulates the activity of cholesterol side chain cleavage enzyme in Leydig cell mitochondria. In contrast, the late steroidogenic lesion is related to the nuclear actions of E2 produced during hormonal action. After hCG stimulation, an increase in nuclear E2 binding was accompanied by an early rise of RNA polymerase activities within 45 min coincident with the maximal increases in circulating testosterone and estradiol levels. These events were followed by the emergence of an E2-induced protein of Mr 27,000 at 3-6 h, and by reduction in the activity of 17 alpha-hydroxylase/17-20 desmolase, and a decrease in microsomal cytochrome P-450.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hormonal regulation of androgen production by the Leydig cell. 632 62

R 5020 (17,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione) is a synthetic analogue of progesterone, which is the physiological hormone that reinitiates germinal vesicle breakdown in Xenopus laevis oocytes. U.v.-driven photoaffinity labelling experiments were conducted with [3H]R 5020 in oocyte subcellular fractions, and covalently bound radioactivity was analysed by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis. In P-10000 (the pellet sedimenting between 1000 and 10000 g and which contains plasma membrane), a major radioactive band migrating as a 30kDa peptide was found. Non-radioactive progesterone competed with the [3H]R 5020 labelling of this fraction, but not with the labelling of minor [3H]R 5020-binding fractions. It displayed the required characteristics of a specific progesterone-binding membrane 'receptor', postulated from previous studies with intact oocytes and with cell-free P-10000 preparations of membrane-bound adenylate cyclase. The apparent Ki of approx. 4 microM for progesterone was compatible with the active concentration of the hormone. Binding specificity, as determined in competition studies, was highly correlated with the germinal vesicle breakdown activity of the steroids and analogues tested. The receptor was not found in the vitelline envelope, in vitelline platelets, in melanosome-enriched or microsomal fractions, in cytosol, nor in germinal vesicles of oocytes. The properties of this membrane steroid receptor are different from those of the already known soluble intracellular steroid receptors, in particular regarding ligand binding specificity and subcellular distribution.
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PMID:Progesterone receptor characterized by photoaffinity labelling in the plasma membrane of Xenopus laevis oocytes. 654 84

Starting at 6 weeks of age, male Fischer 344 rats were provided five different dietary regimens: group 1, fed ad libitum; group 2, restricted to 60% of the food intake of group 1; group 3, restricted to 60% of the food intake of group 1 until 6 months of age and then fed ad libitum; group 4, fed ad libitum until 6 months of age and then restricted to 60% of the food intake of group 1; group 5, given the same caloric intake as group 1 but 60% of the protein intake. The weight of the liver was maintained at about 2.5% of body weight over the wide range of body weight, age (6 through 30 months of age) and diets of this study. Liver cholesterol concentration increased with age in the rats of group 1 but not in the other groups; the hepatic cholesterol concentration was lower in the rats of groups 2 and 4 than in the others. The liver microsomal 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase activity was higher in 4-month-old rats than in rats 12 months of age and older; also, the microsomal activity from group 2 and group 4 rats was higher than that from rats of the other groups. Liver triglyceride levels increased with age in groups 1, 2, 3 and 5 but not in group 4. At all ages, postabsorptive (15 h without food) hepatic glycogen concentrations were much higher in groups 2 and 4 than in the other groups. Liver phospholipid concentration was not affected by age or diet. Basal adenylate cyclase activity in liver homogenates increased with age in all but group 4, but hormone-stimulated adenylate cyclase activity was little affected by age or diet. The age-related hepatic changes in lipids and in hormone responsiveness noted in the present study were much less marked than those previously found in blood and adipose tissue.
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PMID:Age changes in hepatic metabolic characteristics and their modulation by dietary manipulation. 669 41

The Ca2+-dependent regulation of the adenylate cyclase activity associated with microsomes isolated from bovine aortic smooth muscle has been studied. Calmodulin content of microsomal membranes employed in these studies was 80 +/- 14 ng/mg as determined by specific radioimmunoassay. In the absence of exogenous calmodulin, Ca2+ concentrations greater than 0.8 microM inhibited adenylate cyclase activity with one-half-maximal inhibition occurring at 2.5 microM Ca2+. In the presence of 5 or 9 microM bovine testis calmodulin, Ca2+ stimulated smooth muscle adenylate cyclase activity with one-half-maximal stimulation occurring at 0.2 microM for both 5 and 9 microM calmodulin. Calmodulin stimulation was observed between 0.1 and 0.8 microM Ca2+. Despite the presence of calmodulin, Ca2+ concentrations greater than 0.8 microM were inhibitory to smooth muscle adenylate cyclase activity. However, calmodulin reduced the sensitivity of the enzyme to inhibition by Ca2+. Trifluoperazine (100 microM) reversed both the calmodulin-dependent stimulation of cyclase activity and the calmodulin-induced decrease in sensitivity to the inhibitory actions of Ca2+. Trifluoperazine alone shifted the curve describing Ca2+ inhibition of cyclase activity to the left. The value of Ca2+ for one-half-maximal inhibition decreased from 2.9 to 1.2 microM. The trifluoperazine-induced shift was reversed by exogenous calmodulin. These data suggest: 1) Ca2+, at physiological concentrations, can stimulate as well as inhibit smooth muscle adenylate cyclase activity; 2) the stimulation of adenylate cyclase activity is mediated by calmodulin; 3) the Ca2+-calmodulin complex reduces the sensitivity of smooth muscle adenylate cyclase to the inhibitory actions of Ca2+; and 4) the level of calmodulin associated with smooth muscle adenylate cyclase may modulate the response (both stimulatory and inhibitory) of the enzyme to Ca2+.
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PMID:Calmodulin stimulation and calcium regulation of smooth muscle adenylate cyclase activity. 688 7

In almost all cell types, adenylate cyclase is located in the plasma membrane. In lymphocytes, however, this enzyme has been claimed to be largely present in intracellular compartments. In this study, the distribution of adenylate cyclase activity in subcellular fractions of calf thymocytes was reinvestigated by a balance sheet approach. When subcellular fractionation was performed in the absence of ATP and dithiothreitol, less than a half of the homogenate basal activity could be recovered in the fractions, and this amount was distributed almost equally in three main compartments: the plasma membrane fraction, the microsomal and mitochondrial fractions and the nuclear fraction. However, if enzyme activity in the above fractions was measured in the presence of the stimulatory agents NaF, guanylylimidophosphate or guanosine 5'-O-(3-thio)triphosphate, or if the subcellular fractionation was performed in media containing ATP and dithiothreitol, the overall recovered activity greatly increased (up to 90%) and the distribution was shifted in favour of the plasma membrane fraction (up to 65% of the recovered activity). The adenylate cyclase properties were similar in all fractions. The ionophore alamethicin did not alter the subcellular distribution of the enzyme. The localization of adenylate cyclase in thymocytes thus appears to be primarily, if not uniquely, in the plasma membrane, as generally found in other cell types.
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PMID:Subcellular localization of adenylate cyclase in thymocytes. 696 61

It was found that adenylate cyclase from spleen lymphocytes is more active as compared to that from thymocytes, but is less sensitive to the activating effect of epinephrine and NaF. Adenylate cyclase from different subcellular fractions of thymocytes has different sensitivity to NaF. In the microsomal and mitochondrial fractions the enzyme is inhibited by NaF 7- and 2-fold, while in cell lysate and nuclear-cellular fractions it is activated 3- and 9-fold, respectively. In the presence of NaF adenosine, AMP, PPi and methylene diphosphonic acid inhibit the enzyme activity both in thymus and spleen lymphocytes. Creatine and CrP also significantly decrease the enzyme activity. NH4+ and concanavalin A have no effect and phytohemagglutinin stimulates the enzyme from both sources.
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PMID:[Adenylate cyclase from rat thymus and spleen lymphocytes]. 697 32

Effects of 20,25-diazacholesterol (DAC), a myotonia-inducing drug, were evaluated on certain biochemical and morphological properties of embryonic rat muscle cells grown in tissue culture. During DAC treatment, muscle fibers exhibited spontaneous contractions that changed from coarse twitches to finer fibrillation movements, The ultrastructural alterations produced by DAC were smeared Z-lines, disorganized myofibrils, occasional honeycomb appearance of membranes and large vacuoles connected to zipper-like structures. Biochemically, a microsomal fraction prepared from DAC-treated cells (compared to that of normal cells) showed a 30-45 per cent decrease in the isoproterenol-enhanced and the NaF-enhanced adenylate cyclase activity. however, the beta-adrenergic receptors, through which isoproterenol activates the enzyme, showed no change in density or affinity as judged by the binding of [125I]iodohydroxybenzylpindolol. That indicated that DAC treatment caused an uncoupling of beta-receptor-adenylate cyclase interaction. Guanylate cyclase and cyclic GMP-phosphodiesterase were both markedly increased in DAC-treated cells, indicating a greater turnover of cyclic GMP. Binding of [3H]concanavalin A to DAC-treated muscle membranes was decreased 20-40 per cent. The data indicate that DAC exert a direct influence on muscle fibers, affecting their functional, biochemical and morphological properties.
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PMID:Biochemical and morphological effects of 20,25-diazacholesterol on cultured muscle cells. 705 57

The adenylate cyclase activity of Acanthamoeba castellanii (Neff) was studied in extracts prepared after breaking cells in the Potter-Elvehjem homogenizer. The adenylate cyclase activity of cells is low during the exponential growth phase, but then rises 2--4-fold during the stationary phase to a peak, roughly at the time that cyst forms are detectable in the culture. A 2--4-fold activity rise to a peak also occurs 4--8 h after late log cells are transferred to a non-nutrient encystment medium, a time which is shortly before numbers of cyst forms can be detected in the culture. The pattern of activity observed when stationary phase cells are transferred to encystment medium is complex and depends in part on whether the cultures have exhibited the peak of cyclase activity and have begun to initiate cyst formation prior to the transfer. Within the usual time frame after transfer to encystment medium, early logarithmic phase cells do not exhibit a 2--4-fold rise of cyclase activity and they do not encyst. The results suggest a relationship between encystment and the pattern of rise and fall in cyclase specific activity. Fractionation of the homogenate of trophozoites indicated that adenylate cyclase activity was associated with the particulate microsomal fraction.
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PMID:Adenylate cyclase activity during growth and encystment of Acanthamoeba castellanii. 738 35

Metabolic effects of dexamethasone (DX) on the noninfarcted functioning myocardium were studied in rabbits with experimental coronary artery ligation to evaluate the usefulness of glucocorticoids in acute myocardial infarction. Maximum active tension of noninfarcted area of the isolated perfused hearts was markedly reduced 6 hr, 2 days, and 5 days after ligation, associated with significant decreases in norepinephrine (NE) and cAMP contents, but with no changes in adenylate cyclase (AC) and cAMP phosphodiesterase (PDE) activities. Calcium content of mitochondrial fraction was considerably increased in the peri- and noninfarcted area without any changes in microsomal CA2+ or myocardial total Ca2+. Ca2+ uptake rate and Ca2+-dependent ATPase activity of the sarcoplasmic reticulum fraction from the operated hearts were markedly reduced. Intramuscular administration of DX (3 mg/kg body wt/day) for 2 days after operation significantly improved these reductions in myocardial function and metabolism. In normal hearts from animals without infarction, DX caused 48% elevation in basal cAMP level, marked reductions in mitochondria and microsomal Ca2+, and 26% decrease in PDE activity, although no changes in myocardial total Ca2+ AC activity and myocardial contractility were observed. NE-induced inotropic effects were markedly enhanced in both control and operated groups with DX treatment. These results indicated that large doses of DX would improve the reduced myocardial function and metabolism in acute myocardial infarction by increasing basal cAMP level and by its influence on intracellular Ca2+ available for cellular activity.
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PMID:The effects of large doses of dexamethasone on myocardial contractility and calcium metabolism in experimental myocardial infarction. 742 58


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