Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A membrane preparation of calf heart left ventricle has been used to study the effect of radical stress on the beta-adrenoceptor complex. To this end the membranes were incubated for 30 minutes with several concentrations of hydrogen peroxide. This resulted in a dose dependent peroxidation of the membrane lipids. Preincubation with hydrogen peroxide in the concentration range 10(-7)-10(-3) M caused an increase in specific (-)-[125I]-Iodocyanopindolol binding, possibly due to a decrease in membrane fluidity as a result of lipid peroxidation, thus making the receptor protein more accessible. Higher concentrations H2O2 reduced the specific (-)-[125I]-Iodocyanopindolol binding, which is most likely the effect of deterioration of the receptor protein by the more pronounced radical stress induced by these higher concentrations. Also adenylate cyclase activity was affected by radical stress. Basal cyclic-AMP production and cyclic-AMP production induced by NaF (10(-2) M) or guanylylimidodiphosphate (10(-4) M), was suppressed after pretreatment with concentrations of H2O2 above 10(-4) M. This indicates a higher sensitivity of the adenylate cyclase toward radical stress when compared to the receptor protein. Our results show that radical stress can perturb beta-adrenoceptor function considerably in the heart.
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PMID:The effect of hydrogen peroxide on beta-adrenoceptor function in the heart. 285 25

We have determined the effects of tetradecanoyl phorbol acetate (TPA) and of the calcium ionophore A23187 on two thyroid responses to TSH previously reported to be cAMP-independent. We observed that TPA and A23187, at doses of 1.0 microM, stimulated both hydrogen peroxide generation and glucose oxidation in calf thyroid slices. A subthreshold dose of A23187 (0.1 microM) added to a submaximal dose of TPA (0.5 microM) acted synergistically, stimulating H2O2 production to the same degree as a maximally effective dose of TSH (50 mU/ml). Forskolin (25 microM), a direct stimulator of adenylate cyclase, actually inhibited both glucose oxidation and hydrogen peroxide generation. Lithium chloride (25 mM) had no effect on either response, either in the basal state or with TSH stimulation. The calcium channel antagonist verapamil (50 microM) decreased the basal activity of glucose oxidation and peroxide generation but did not substantially inhibit the effect of TSH on H2O2 generation under the conditions studied. These data support the concept that TSH induces changes in the thyroid phosphatidylinositol metabolism which activates protein kinase-C (c-kinase) and raises cytosolic free calcium. These events appear to act in concert to mediate certain metabolic responses in differentiated thyroid tissue.
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PMID:Peroxide formation and glucose oxidation in calf thyroid slices: regulation by protein kinase-C and cytosolic free calcium. 300 9

Low density lipoprotein (LDL) isolated from sera of healthy volunteers in 50 micrograms protein/ml concentration induced an early adenylate cyclase activation in human monocytes followed by elevation of cGMP level. In addition, a rapid 45Ca2+ influx was also detected on addition of 25-100 micrograms protein/ml concentrations. The monocyte activating effect of LDL under in vitro circumstances was characterized by an enhanced O2 consumption, H2O2 generation and by the increased release of lysosomal enzymes such as beta-glucuronidase and elastase like protease (ELP). On the other hand, LDL diminished markedly the Fc gamma receptor (Fc gamma R) mediated rosette formation, phagocytosis and the antibody dependent cellular cytotoxicity (ADCC) of monocytes without a significant decrease in the IgG binding capability of cells. High levels of serum LDL may play a significant role in the arterial wall injury by elastase like protease as well as biologically active oxygen species released from monocytes of patients suffering from arteriosclerosis.
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PMID:Immunomodulating effect of low density lipoprotein on human monocytes. 302 82

A model for the regulation of erythropoietin production has been presented. This model proposes that a primary O2-sensing reaction in the kidney is initiated by a decrease in ambient PO2, a rapid decrease in gas exchange in the lung, a diminished oxygen-carrying capacity of hemoglobin, a molecular deprivation of oxygen, or a decrease in renal blood flow. It is proposed that the primary oxygen-sensing reaction may trigger the release of several mediators that stimulate adenylate cyclase through a receptor-activated stimulation of a G protein in the renal cell membrane. Some of the agents that are thought to be released during hypoxia, which may trigger this cascade, are adenosine (A2 activation), eicosanoids (PGE2, PGI2, and 6-keto PGE1), oxygen-free radicals (superoxide and H2O2), and catecholamines with beta-2 adrenergic receptor agonist properties. The activation of adenylate cyclase generates cyclic AMP, which activates protein kinase A, leading to the production of a phosphoprotein that, in turn, activates a nuclear protein involved in transcription and/or translation for erythropoietin biosynthesis and/or secretion. A second part of this model concerns the effect of hypoxia on a renal cell membrane phosphodiesterase and the generation of inositol triphosphate and diacylglycerol. Diacylglycerol may interact with diacylglycerol lipase to generate arachidonic acid, which, together with arachidonic acid generated by the interaction of phospholipase A2 on membrane phospholipids, produces eicosanoids. Eicosanoids may play a secondary role in Ep production/secretion. The model further proposes that calcium levels in both renal and liver cells may be important in regulating erythropoietin biosynthesis and/or secretion. It is proposed that an increase in intracellular calcium leads to the inhibition of erythropoietin biosynthesis and/or secretion and a decrease in intracellular calcium increases erythropoietin production. The specific mechanism by which calcium regulates erythropoietin biosynthesis and secretion is not well understood. However, a good correlation is seen with several agents that decrease intracellular calcium and increase erythropoietin production as well as with other agents that increase intracellular calcium and decrease erythropoietin production. When inositol triphosphate levels are increased, an increase in the mobilization of intracellular calcium from the endoplasmic reticulum or another intracellular pool occurs. This increased intracellular calcium probably activates a calcium calmodulin kinase and produces a phosphoprotein that inhibits erythropoietin production/secretion.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pharmacologic modulation of erythropoietin production. 328 82

The effect of sulfhydryl compounds on binding of the beta-adrenergic antagonist (-)-[3H]dihydroalprenolol [(-)-[3H]DHA] to a microsomal fraction from rabbit skeletal muscle was examined. Inhibition of binding by a variety of adrenergic agonists and antagonists and the effects of these agents on adenylate cyclase were consistent with the beta-adrenergic receptor in this tissue being of the beta 2-subtype. Binding of (-)-[3H]DHA was reduced by incubating the membranes with dithiols such as dithiothreitol (DTT), 1,3-dimercapto-2-propanol and 1,4-dimercaptobutane; monothiols were much less potent. DTT-induced decline in (-)-[3H]DHA binding resulted primarily from a decrease in receptor number. Inactivation was partially reversed by the oxidant H2O2. Binding sites could be locked in the inactivated state by incubating DTT-treated membranes with the alkylating agent iodoacetamide. Both beta-adrenergic agonists and antagonists protected against inactivation. Adenylate cyclase activity in the membranes was increased by DTT. The enzyme was rapidly inactivated by H2O2, and this could be partially reversed by DTT. It is concluded that the beta-adrenergic receptor of skeletal muscle contains an essential disulfide moiety which can be inactivated by reducing dithiols. Adenylate cyclase, on the other hand, contains at least one essential sulfhydryl which is preserved by dithiols.
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PMID:Inactivation of the beta-adrenergic receptor in skeletal muscle by dithiols. 613 19

The effects of the reducing agent dithiothreitol (DTT) on vasopressin (AVP)-stimulated osmotic water flow and adenylate cyclase activity were studied in the urinary bladder of Bufo marinus. DTT produced concentration-dependent inhibition of the hydroosmotic water permeability response to 10 mU/ml AVP and 10 mM theophylline but did not inhibit the response to 10 mM adenosine 3',5'-cyclic monophosphate (cAMP). The inhibitory effects of DTT on AVP responsiveness were partially reversed by washing in DTT-free Ringer solution or by addition of oxidizing agents such as dehydroascorbic acid (DHA) or H2O2. The inhibitory effects of DTT were completely reversed by washing in DTT-free Ringer plus addition of DHA. In addition, the inhibitory effects of DTT on AVP-induced osmotic water flow were partially reversed by the GTP analogue 5'-guanylyl imidodiphosphate [Gpp(NH)p]. DTT also inhibited the adenylate cyclase response to AVP but did not alter the response to AVP plus Gpp(NH)p or the response to NaF. These observations suggest that the inhibitory effect of thiol compounds on AVP responsiveness may be modulated through alterations of a redox system distal to the hormone receptor but proximal to the catalytic subunit of adenylate cyclase. Inasmuch as Gpp(NH)p partially reversed the inhibitory effects of DTT on AVP-stimulated osmotic water permeability and prevented the inhibitory effect of DTT on AVP-stimulated adenylate cyclase, an effect on either GTPase or binding of GTP to the regulatory protein of adenylate cyclase is suggested by these observations.
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PMID:Modulation of vasopressin action by reducing agents in Bufo marinus. 628 8

Recent studies have shown that oxidation of bovine PTH-(1-34) [bPTH-(1-34)] with H2O2 abolished the vascular effects of PTH in rats and dogs, but the hypercalcemic effect of the oxidized PTH was preserved in the Japanese quail in vivo. These observations seem at variance with previous studies from our laboratory in the isolated perfused canine tibia preparation in which no uptake of immunoreactive PTH or stimulation of cAMP release was demonstrated during infusion of oxidized bPTH-(1-34). The present studies examine the skeletal and renal effects of oxidized PTH-(1-34) in rats and dogs in vivo. Oxidation of PTH with H2O2 reduced its activation of adenylate cyclase by 95% in dog renal cortical membrane. Awake normal dogs were studied before and during the infusion of bPTH-(1-34) or oxidized PTH-(1-34) (4 U/kg X h). With active PTH, ionized Ca+2 rose in each dog (range, 0.7-1.5 mg/dl), while with oxidized PTH, Ca+2 remained within 0.1 mg/dl of the baseline values. Fractional excretion of PO4 rose from 1.58 +/- 0.6% to 29.5 +/- 2.5% with active PTH and from 1.4 +/- 0.4% to 5.7 +/- 1% with oxidized PTH. The latter did not differ from the value in vehicle-infused dogs. Further studies were performed in 30 acutely parathyroidectomized rats. Plasma Ca+2 rose from 8.2 +/- 0.1 to 9.0 +/- 0.3 mg/dl with active PTH (20 micrograms/kg), fell to 7.7 +/- 0.2 with oxidized PTH, and fell to 7.3 +/- 0.3 mg/dl with vehicle. In parathyroid-intact rats plasma Ca+2 increased by 0.9 mg/dl whether given active PTH, oxidized PTH, or vehicle. We conclude that oxidation of bPTH-(1-34) results in loss of both the renal and skeletal effects of PTH in vivo in rats and dogs.
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PMID:Absence of biological effects of oxidized parathyroid hormone-(1-34) in dogs and rats. 649 71

Parathyroid hormone (PTH: synthetic bovine, amino terminus 1-34 amino acids) demonstrates a positive inotropic action on the isolated papillary muscle of the rat heart. The effect was evident at PTH concentration of 10(-12)M, and the maximum inotropic effect occurred with PTH concentrations greater than 10(-11)M. Biologically inactive PTH (PTH treated with H2O2) was without effect. The inotropic effect of PTH was partially blocked by propranolol and also suppressed in the papillary muscle of the rat pretreated with reserpine. Methoxyverapamil completely blocked the inotropic action of PTH. PTH was without effects on adenylate cyclase activity of the myocardium. Results show the presence of an inotropic action of PTH in vitro and suggest that this action of PTH is partially mediated by releasing the endogenous myocardial norepinephrine which exerts a positive inotropic effect via beta-adrenergic stimulation and by an increase in Ca++ influx across plasma membranes, but independent of adenylate cyclase activation. The inotropic action of PTH may be of significance in normal cardiac function.
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PMID:Parathyroid hormone has a positive inotropic action in the rat. 730 51

Neutrophil-derived hydrogen peroxide (H2O2) is believed to play an important role in inflammatory lung injury. We investigated the influence of pharmacological agents that increase intracellular c-AMP levels on endothelial and epithelial leakage in response to intravascular H2O2 challenge in buffer-perfused rabbit lungs. Endothelial permeability was assessed by determination of the capillary filtration coefficient (Kfc) and lung weight gain. Measurement of the clearance rate of inhaled aerosolized technetium-99m-labeled diethylenetriamine pentaacetic acid ([99mTc]DTPA) from the lungs into the perfusion fluid was used as an index of alveolar epithelial permeability. Experiments were performed in the presence of acetylsalicylic acid to suppress H2O2-induced lung prostanoid generation and concomitant vasoconstriction. Under these conditions, H2O2 admixture to the perfusate (250 microM) caused a greater than eight-fold increase in Kfc values, resulting in > 30 g lung weight gain within 30 min in the absence of any significant vasopressor response. Pretreatment with the adenylate cyclase activators prostaglandin E1 (0.1 microM) and forskolin (0.1 microM), the dual phosphodiesterase type III/IV inhibitor zardaverine (10 microM) as well as combinations of these drugs all caused a nearly complete suppression of this early Kfc increase; and severe edema formation (> 30 g) was retarded to approximately 50-55 min. In addition to the microvascular leakage response, H2O2 caused a four- to five-fold increase in the [99mTc]DTPA clearance rate, starting within 15 min and culminating after approximately 35 min. Adenylate cyclase activation reduced this epithelial leakage response by approximately 30%, whereas zardaverine exerted no significant effect. We conclude that both microvascular endothelial and alveolar epithelial barrier function are severely compromised by intravascular H2O2 challenge in intact lungs. Pharmacological approaches to increase c-AMP levels, including both adenylate cyclase activation and phosphodiesterase inhibition, partially block the endothelial response and, to a lesser extent, the epithelial response.
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PMID:Hydrogen peroxide-induced increase in lung endothelial and epithelial permeability--effect of adenylate cyclase stimulation and phosphodiesterase inhibition. 747 70

1. Recent studies have suggested that the generation of nitric oxide (NO) and hydrogen peroxide (H2O2) by islet NO synthase and monoamine oxidase, respectively, may have a regulatory influence on insulin secretory processes. We have investigated the pattern of insulin release from isolated islets of Langerhans in the presence of various pharmacological agents known to perturb the intracellular levels of NO and the oxidation state of SH-groups. 2. The NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) dose-dependently increased L-arginine-induced insulin release. D-Arginine did not influence L-arginine-induced insulin secretion. However, D-NAME which reportedly has no inhibitory action on NO synthase, modestly increased L-arginine-induced insulin release, but was less effective than L-NAME. High concentrations (10 mM) of D-arginine as well as L-NAME and D-NAME could enhance basal insulin release. 3. The intracellular NO donor, hydroxylamine, dose-dependently inhibited insulin secretion induced by L-arginine and L-arginine+L-NAME. 4. Glucose-induced insulin release was increased by NO synthase inhibition (L-NAME) and inhibited by the intracellular NO donor, hydroxylamine. Sydnonimine-1 (SIN-1), an extracellular donor of NO and superoxide, induced a modest suppression of glucose-stimulated insulin release. SIN-1 did not influence insulin secretion induced by L-arginine or the adenylate cyclase activator, forskolin. 5. The intracellular 'hydroperoxide donor' tert-butylhydroperoxide in the concentration range of 0.03-3 mM inhibited insulin release stimulated by the nutrient secretagogues glucose and L-arginine. Low concentrations (0.03-30 microM) of tert-butylhydroperoxide, however enhanced insulin secretion induced by the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX). 6. Islet guanosine 3':5'-cyclic monophosphate (cyclic GMP) content was not influenced by 10 mML-arginine or tert-butylhydroperoxide at 3 or 300 micro M but was markedly increased (14 fold) by a high hydroxylamine concentration (300 micro M). In contrast, islet adenosine 3':5'-cyclic monophosphate (cyclicAMP) content was increased (3 fold) by L-arginine (10 mM) and (2 fold) by tert-butylhydroperoxide(300 micro M).7. Our results strongly suggest that NO is a negative modulator of insulin release induced by the nutrient secretagogues L-arginine and glucose. This effect is probably not mediated to any major extent by the guanylate cyclase-cyclic GMP system but may rather be exerted by the S-nitrosylation of critical thiol groups involved in the secretory process. Similarly the inhibitory effect of tert-butylhydroperoxide is likely to be elicited through affecting critical thiol groups. The mechanism underlying the secretion promoting action of tert-butylhydroperoxide on IBMX-induced insulin release is probably linked to intracellular Ca2+-perturbations affecting exocytosis.8. Taken together with previous data the present results suggest that islet production of low physiological levels of free radicals such as NO and H202 may serve as important modulators of insulin secretory processes.
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PMID:Influence of nitric oxide synthase inhibition, nitric oxide and hydroperoxide on insulin release induced by various secretagogues. 753 13


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