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)

Patients with atopic dermatitis have abnormal autonomic responses of the arterioles, pilomotor smooth muscle, and sweat glands. Their lesions have been reported to contain increased amounts of the neurohumors, acetylcholine and norepinephrine, as well as increased activity of acetylcholinesterase and catechol-O-methyltransferase. In vitro studies of epidermis show that beta adrenergic agonists fail to evoke the normal inhibition of mitosis of basal cells of patients with atopic dermatitis. Epidermis removed not only from the lesions, but also from normal-appearing skin, responded abnormally. The increase in intracellular levels of cAMP after exposure to catecholamines was similar in normal and atopic epidermis. Lymphocytes and PMN leukocytes isolated from patients with atopic dermatitis show both a decreased physiologic response (glycogenolysis and inhibition of lysosome enzyme release) and a decreased rise in intracellular levels of cAMP upon incubation with beta agonists, but a normal response to PGE1. Cortisol increases the response of lymphocyte adenyl cyclase to both agonists and, in the case of the patients with atopic disease, more than overcomes the depressed response to beta agonists. Because the leukocytes respond normally to PGE1 and because others have reported normal activities of skin and adenyl cyclase, phosphodiesterase, and protein kinases, we conclude that the step responsible for the diminished beta adrenergic response lies antecedent to the catalytic site of adenyl cyclase.
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PMID:Adrenergic mechanisms and the adenyl cyclase system in atopic dermatitis. 0 56

Effects of adrenalectomy and acute insulin insufficiency upon tissue adenosine 3', 5' cyclic monophosphate concentrations, and adenyl cyclase, phosphodiesterase, and protein kinase activities were investigated. Adrenalectomy decreased intracellular adenosine 3', 5' cyclic monophosphate 53% and increased the activities of both adenylcyclase and phosphodiesterase. Cortisol therapy returned these to normal. During insulin insufficiency caused by anti-insulin serum, mammary adenosine 3', 5' cyclic monophosphate concentrations increased. The acute effects of insulin insufficiency and chronic effects of adrenelectomy suggest that insulin acts upon rat mammary glands to decrease and glucocorticoids, acting over longer term, to increase adenosine 3', 5' cyclic monophosphate concentrations.
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PMID:Effect of adrenalectomy and insulin insufficiency upon the adenosine 3', 5' cyclic monophosphate system of the rat mammary glands. 16 26

Human synovial fibroblasts in culture respond to bradykinin with a 20-fold increment in intracellular cyclic AMP concentrations, however bradykinin does not directly activate adenylate cyclase activity in a particulate fraction derived from these cells. Bradykinin evokes a release of labeled arachidonic acid and prostaglandins E and F from synovial fibroblasts pre-labeled with 3H-arachidonic acid. Hydrocortisone inhibits the bradykinin induced increment in cyclic AMP and the release of arachidonic acid and prostaglandins E and F from synovial fibroblasts. Indomethacin, which also inhibits the cyclic AMP response to bradykinin, has no effect on the release of arachidonic acid from synovial fibroblasts. Indomethacin does, however, inhibit the quantity of prostaglandins released into the medium. These studies support the hypothesis that bradykinin does not activate human synovial fibroblast adenylate cyclase, but presumably activates a phospholipase whose products in turn result in the synthesis of prostaglandins. These and other investigations also suggest that a product(s) of the prostaglandin pathway causes the increment in cyclic AMP.
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PMID:Hydrocortisone inhibition of the bradykinin activation of human synovial fibroblasts. 19 75

The effects of cortisol on the natural killer (NK) activity of human peripheral blood mononuclear (PBM) cells were studied in vitro using a direct 4-h 51Cr-release assay and K 562 cell line as a target. Preincubation for 20 h of PBM cells drawn from healthy donors with 1 X 10(-8) to 1 X 10(-5) M cortisol resulted in a significant decrease of NK cell activity. The magnitude of the suppression was directly related to the steroid concentration and inversely related to the number of effector cells. Cortisol was able to minimize the enhancement of NK cytotoxicity obtainable in the presence of immune interferon (IFN-gamma). A significantly higher suppression was achieved after sequential exposure of PBM cells to cortisol and equimolar levels of prostaglandin E2 (PgE2). The concomitant incubation with theophylline and isobutyl-methylxanthine failed to enhance the cortisol-induced suppression, whereas PgE2-dependent inhibition significantly increased after exposure of PBM cells to methyl-xanthines. The inhibitory effect of cortisol was partially or totally prevented by the concomitant incubation with equimolar amounts of 11-deoxycortisol and RU 486 but not of progesterone. Treatment of NK effectors with a monoclonal anti-human corticosteroid-binding globulin (CBG) antibody produced an enhancement of the spontaneous NK activity and a partial suppression of cortisol-mediated effects. Our results suggest that endogenous glucocorticoids play a role in the regulation of NK cell-mediated cytotoxicity. Since the effect of cortisol was additive to that of PgE2 and was not changed by phosphodiesterase inhibitors, it is conceivable that the hormone acts at a level different from the adenylate cyclase-phosphodiesterase system. Data obtained with the use of antiglucocorticoids and the anti-CBG antibody are compatible with a role both of high-affinity glucocorticoid receptors and of CBG in mediating cortisol action on the human NK cell activity.
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PMID:Inhibition by cortisol of human natural killer (NK) cell activity. 243 32

The aim of this study was to investigate quantitatively the action of and the interaction between beta-adrenergic receptor agonists in desensitizing guinea pig isolated trachea. It was also to evaluate the influence of substances whose effects on desensitization are either disputed (theophylline, indomethacin, ketotifen, hydrocortisone) or unknown (nicardipine, Bay K 8644, fenspiride, adenosine). Tracheal strips were contracted with histamine (5 x 10(-5) M) or acetylcholine (5.10(-5) M) and concentration-response (C/R) curves for various beta-adrenoceptor agonists were determined before and after incubation (20 min to 4 h) with the same beta-adrenoceptor agonist (autodesensitization), with other beta-adrenoceptor agonists (cross-desensitization), or with a beta-adrenoceptor agonist and another substance. Our results show that the autodesensitization induced by isoprenaline is concentration dependent and that concentration dependence is more pronounced with salbutamol and fenoterol than with isoprenaline and adrenaline with respect to autodesensitization: shifts (log unit) of the C/R curves were 0.59 +/- 0.06 (N = 5) for salbutamol (10(-5) M), 0.78 +/- 0.09 (N = 5) for fenoterol (10(-6) M), 0.30 +/- 0.04 (N = 9) for isoprenaline (10(-5) M), and 0.33 +/- 0.05 (N = 5) for adrenaline (10(-5) M). Our studies of cross-desensitization (desensitization to isoprenaline, adrenaline, salbutamol, and fenoterol induced by incubation with isoprenaline 10(-5) M) showed a significantly greater shift in the C/R curves for fenoterol (0.56 +/- 0.08, N = 5) and salbutamol (0.62 +/- 0.05, N = 5) than for adrenaline (0.35 +/- 0.07, N = 5) and isoprenaline itself (0.30 +/- 0.05, N = 9). Of the substances we studied, none modified the desensitization induced by isoprenaline except hydrocortisone and adenosine. Hydrocortisone (10(-8) M) reduced it significantly, although to a negligible extent. Adenosine (3 x 10(-4) M) did not shift the C/R curve to isoprenaline by itself, but incubation of tracheal strips with adenosine and isoprenaline caused a significantly greater shift of C/R curves to isoprenaline (0.30 +/- 0.04) than incubation with isoprenaline alone (0.20 +/- 0.04) (P less than 0.05, N = 5). These experiments suggest that adenosine may have increased the uncoupling and/or down-regulation phenomena induced by isoprenaline, or modified adenylate cyclase-cAMP activity.
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PMID:In vitro desensitization of beta-adrenoceptors in guinea pig trachea: interactions between beta-adrenoceptor agonists and influence of adenosine and other drugs. 256 70

A system of calf thyroid follicular cells in primary cultures has been developed to investigate the control of thyroglobulin gene expression in normal cells in vitro. In low (0.1%) serum conditions, the cells remained quiescent and formed dense aggregates surrounded by slowly spreading cells. High expression of thyroid-specific differentiation markers such as thyroglobulin (Tg) mRNA accumulation and iodide transport required the continuous exposure of cells to thyrotropin (TSH) or other adenylate cyclase activators (cholera toxin and forskolin). In the absence of TSH, Tg mRNA decreased to low but still detectable levels. Addition of TSH, forskolin or cholera toxin restored high Tg gene expression. Hydrocortisone moderately stimulated basal Tg mRNA accumulation and strongly potentiated the effect of TSH. Growth promoters including serum (1-10%), epidermal growth factor (EGF), fibroblast growth factor (FGF) and 12-O-tetradecanoylphorbol 13-acetate (TPA) induced calf thyroid cells to develop as a monolayer and inhibited both basal and TSH-stimulated expression of specialized functions. Moreover, only a partial restoration of this expression was achieved after addition of TSH or forskolin to well spread-out cells that had proliferated in response to EGF or serum. The results show that in calf thyroid cells, iodide transport and Tg gene expression are regulated by TSH through cyclic AMP; hydrocortisone potentiates this effect on Tg gene expression, while all growth promoting factors inhibit the expression of these differentiated functions.
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PMID:Thyroglobulin gene expression as a differentiation marker in primary cultures of calf thyroid cells. 266 67

Thyroid hormone regulation of beta-adrenergic receptor-coupled adenylate cyclase activity was studied in rat liver and heart particulate fractions. Thyroidectomy (Tx) increased isoproterenol-stimulated cAMP accumulation in the liver and decreased it in the heart. Administration of L-thyroxine (L-T4) or L-3,3',5-triiodothyronine (L-T3) reversed these changes in both liver and heart. The changes observed in liver beta-receptor-coupled adenylate cyclase activity after Tx were similar to those reported after adrenalectomy (ADX). Thus the hypothesis was considered that these changes with altered thyroid status are produced indirectly through alteration in adrenal corticosteroids. Hydrocortisone in Tx rats decreased liver isoproterenol-stimulated adenylate cyclase activity but had no significant effect on the heart. Serum corticosterone levels were decreased significantly (by 34%) in Tx rats, as compared to euthyroid rats. Administration of L-T4 to Tx rats doubled the serum corticosterone levels. In Tx-ADX rats, L-T4 had no significant effect on liver beta-receptor-coupled adenylate cyclase. However, L-T4 significantly increased heart beta-receptor-coupled adenylate cyclase in these animals. Dexamethasone, but not deoxycorticosterone, decreased liver isoproterenol-stimulated cAMP accumulation in Tx animals to the same extent as was observed with L-T4 and hydrocortisone. Thus overall the results indicate that in the liver, as opposed to the heart, thyroid hormones regulate beta-adrenergic receptor-coupled adenylate cyclase indirectly through corticosteroids. Glucocorticoid rather than mineralocorticoid activity seems to be responsible for this regulation.
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PMID:Differential regulation of beta-adrenergic receptor-coupled adenylate cyclase by thyroid hormones in rat liver and heart: possible role of corticosteroids. 282 Aug 55

Cultured C6 rat glioma cells contain mRNA coding for preproenkephalin (A), the precursor of methionine- and leucine-enkephalin. The abundance in untreated cells was determined by blot hybridization methods to be 3-6 pg per micrograms total RNA. Treatment of confluent cells for 12 h with 10 microM (-)-norepinephrine, which activates C6 adenylate cyclase, transiently elevated preproenkephalin mRNA to 3.3 and 7.7 times the control in the absence and presence of the glucocorticoid dexamethasone, respectively. Hydrocortisone and corticosterone also potentiated the effect of norepinephrine. However, glucocorticoids alone did not alter the preproenkephalin mRNA abundance. The effect of norepinephrine + dexamethasone was blocked by the beta-adrenergic antagonist propranolol but not by the alpha-adrenergic antagonist phentolamine. Forskolin, which directly activates adenylate cyclase, similarly elevated the preproenkephalin mRNA abundance; its effect was also potentiated by dexamethasone. C6 cells contain Met-enkephalin-containing protein resembling proenkephalin (apparent Mr 30,000) but little Met-enkephalin, suggesting a low level of proper precursor processing. Treatment with norepinephrine + dexamethasone raised the content of proenkephalin-like protein 11-fold. Thus, preproenkephalin mRNA levels in C6 cells are regulated synergistically by adenosine 3':5'-cyclic monophosphate and glucocorticoids. These results suggest modes of regulation of proenkephalin biosynthesis in normal rat enkephalinergic cells.
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PMID:Expression of the enkephalin precursor gene in C6 rat glioma cells: regulation by beta-adrenergic agonists and glucocorticoids. 287 71

The present study examines the effect of chronic treatment with glucocorticoids on the steroidogenic activity of ovine adrenocortical cells in vitro. Cells cultured in the presence of 10(-9) to 10(-5) M dexamethasone produced more glucocorticosteroids in response to ACTH1-24, forskolin or 8 BrcAMP than did control cells. Such an enhancing effect required more than 5 h of treatment and was maximal at 30 h; it was both concentration-dependent and steroid-specific. The maximal secretion of corticosteroids was observed when cells were exposed to 10(-7) M dexamethasone; with higher concentrations the response to ACTH1-24 decreased steadily; the ED50 was 2.8 +/- 0.8 nM. Cortisol and corticosterone enhanced ACTH1-24-induced steroidogenesis to the same extent as dexamethasone, but at concentrations roughly 100-fold higher than for dexamethasone. Testosterone and 17 beta-oestradiol had no enhancing effect. Dexamethasone not only enhanced the maximal steroidogenic response to ACTH1-24 but also decreased its ED50 3-fold. Treatment of cultures with the antiglucocorticoid RU 38486 resulted in a dose-dependent, time-dependent, decrease in ACTH1-24-induced corticosteroid output. Moreover, RU 38486 antagonized the enhancing effect of dexamethasone. The production of corticosteroids by dexamethasone-treated cells incubated in the presence of 22(R)-hydroxycholesterol or of exogenous pregnenolone was similar to that of control cells. The enhancing effect of dexamethasone was also observed when cultures were performed in the absence of insulin and/or in serum-free media. These data suggest that chronic exposure to glucocorticoids is necessary for the full steroidogenic activity of ovine adrenocortical cells. Moreover, they indicate that glucocorticoids exert their effect at least at two different levels in the cell: (i) on the adenylate cyclase system and (ii) at step(s) beyond cAMP but before pregnenolone formation.
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PMID:Glucocorticoid enhancement of glucocorticoid production by cultured ovine adrenocortical cells. 319 Nov 65

Plasma membrane sacs of isolated rat fat cells (ghots) possess an adenyl cyclase system, which is activated by lipolytic hormones of disparate molecular structure, including adrenocorticotropin (ACTH), glucagon, and epinephrine. Previous studies indicated that distinctive selectivity units for individual hormones are coupled to the same unit of adenyl cyclase in the fat cell membrane. The present study has shown that ghost cyclase from adrenalectomized and hypophysectomized rats exhibits a striking reduction in response to ACTH, the stimulatory effects of epinephrine, glucagon, or fluoride being unchanged. Pretreatment of adrenalectomized, hypophysectomized, sham operated, or intact rats with the synthetic glucocorticoid, dexamethasone, selectively increased the ACTH response in ghost cyclase preparations. Cortisol, like dexamethasone, increased the ACTH response in ghosts from adrenalectomized rats; 11-deoxycorticosterone was ineffective. The dexamethasone effect to enhance the ACTH response is blocked by actinomycin D or cycloheximide. The present results show that stimulation of rat fat cell adenyl cyclase by ACTH involves a distinctive molecular entity, which can be clearly differentiated from adenyl cyclase in the membrane as well as from the selectivity sites for epinephrine and glucagon. The data indicate that the biosynthesis of the component required for ACTH stimulation of ghost cyclase-either an ACTH selectivity unit or specific coupling factor-is induced by glucocorticoids at the level of gene regulation.
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PMID:Glucocorticoid regulation of ACTH sensitivity of adenyl cyclase in rat fat cell membranes. 431 84


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