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)

Erythropoietin (EPO) is mainly produced in the kidneys and is regulated by blood oxygen availability. Studies with isolated perfused kidneys have established that an oxygen-sensing system exists intrarenally but the mechanisms involved are poorly understood. Using a quantitative RNase protection assay, we have demonstrated oxygen-dependent EPO mRNA production in isolated perfused rat kidneys, with EPO mRNA levels increasing 30-fold when perfusate pO2 was reduced from 474 to 25 mm Hg. To determine if the high amplitude changes in EPO mRNA levels in response to hypoxia are mediated by cyclic AMP, four agents, which activate the cyclic AMP system in different ways, were administered to isolated kidneys perfused over a range of perfusate pO2. Salbutamol and N6-ethyl carboxamidoadenosine, which activate adenylate cyclase, dibutyryl cyclic AMP (a cyclic AMP analogue) and forskolin did not augment EPO mRNA production, and no significant differences in the regression of log (EPO mRNA) on perfusate pO2, were found between experimental groups exposed to each of these compounds and controls. We conclude that the rapid increase in EPO mRNA levels in response to hypoxia is not mediated or substantially modulated by a cyclic AMP-dependent mechanism.
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PMID:Rapid oxygen-dependent changes in erythropoietin mRNA in perfused rat kidneys: evidence against mediation by cAMP. 132 27

Erythropoietin is a glycoprotein factor which specifically regulates the proliferation and differentiation of erythroid progenitor cells. We have investigated here the biochemical mechanisms of erythroid differentiation on mouse erythroleukemia SKT6 cells which can be induced to differentiate either with erythropoietin or dimethyl sulfoxide (Me2SO). cAMP-elevating agents, such as forskolin and 3-isobutyl-1-methyl-xanthine, caused spontaneous erythroid differentiation, and these agents showed the stimulatory effects on erythropoietin- or Me2SO-induced differentiation. An adenylate cyclase inhibitor, 2',5'-dideoxyadenosine, blocked erythropoietin-induced differentiation. The intracellular cAMP level was rapidly increased by addition of erythropoietin but not by Me2SO. These observations suggest that erythroid differentiation induced by erythropoietin is mediated, at least in part, through the cAMP-dependent pathway. When the effect of erythropoietin and Me2SO on the intracellular Ca2+ level was examined using fura 2, no acute change was observed. Measurements of the levels of inositol 1,4,5-trisphosphate and diacylglycerol following stimulation with erythropoietin or Me2SO showed that phosphatidylinositol turnover did not change significantly after erythropoietin stimulation but decreased gradually after Me2SO induction. Taken together, these results indicate that a complex signaling network including the cAMP-dependent pathway is involved in the erythroid differentiation process.
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PMID:Transmembrane signaling during erythropoietin- and dimethylsulfoxide-induced erythroid cell differentiation. 217 31

The review provides a survey of current knowledge about the changes in hormone-sensitive adenylate cyclase complex of erythroid cells. The basal enzyme activity decreases continuously during differentiation and maturation. Guanine nucleotides (GTP and GMP-P (NH)P) increase the adenylate cyclase activity of both early and late rabbit bone marrow erythroblasts. The stimulating effect of the beta 2-adrenergic drugs such as L-isoprenaline is limited to the immature cells. L-noradrenaline, a beta 1-agonist is inactive. The lack of response of non-dividing rabbit erythroblasts to beta-adrenergic stimuli is not due to loss of beta-receptors during differentiation, but to a decrease in the effectiveness of the coupling between the components of the system: receptor-guanine nucleotide regulatory protein-catalytic subunit. Prostaglandins E1 and E2 consistently enhance adenylate cyclase activity of erythroblasts on different stages of development. Erythropoietin (0.2 U/ml) causes a transient increase in the activity of adenylate cyclase, which is maximal by 20 min incubation of the cells in the presence of the hormone and disappears within 4 hours. The magnitude of the response to erythropoietin depends on the stage of erythroid cell development and is inverse related to the extent of previous hormonal stimulation of the cell.
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PMID:Adenylate cyclase system of differentiating erythroid cells. 228 99

The involvement of adenylate cyclase in the response elicited by erythropoietin was investigated in fractionated erythroblasts obtained from anaemic rabbit bone marrow. Addition of 0.2 U/ml erythropoietin to cell cultures caused a transient increase in the activity of plasma membrane adenylate cyclase, which was observed within 5 minutes, was maximal by 20 minutes and disappeared within 4 hours. The magnitude of the response to hormonal stimulation depended on the stage of erythroid cell development and was greater in the more immature cells. Erythropoietin could also stimulate the basal activity of adenylate cyclase in an in vitro assay containing plasma membranes of immature, but not mature, erythroid cells. The degree of activation was hormone-concentration dependent, was maximal at 0.2-0.5 U/ml erythropoietin (5-12 nM) and was observed in the absence of exogenous guanine nucleotides. The in vitro effect of erythropoietin, however, was abolished by GDP (S) and extensive washing of the membranes made hormone action GTP-dependent. The ability of the hormone to stimulate adenylate cyclase activity in vitro was inversely related to the extent of hormonal stimulation in vivo. This desensitization was observed within 20 minutes and persisted for many hours. It is suggested that erythropoietin activates the adenylate cyclase of immature erythroblasts via a receptor and a guanine nucleotide-binding protein with high affinity for GTP.
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PMID:The effect of erythropoietin on the adenylate cyclase activity of rabbit bone marrow erythroblasts. 359 94

The effect of two agents of erythroid cell differentiation on the adenylate cyclase activity of fractionated rabbit bone marrow erythroblasts has been investigated. Addition of 0.2U/ml erythropoietin to cell cultures causes a transient increase in the activity of plasma membrane adenylate cyclase, which is maximal by 20 min and disappears within 4 h. The magnitude of the response to hormonal stimulation depends on the stage of erythroid cell development and is greater in the more immature cells. Addition of 50 microM haemin to cultures of erythroblasts also causes an increase in the activity of adenylate cyclase, which differs from the effect of erythropoietin in kinetics and specificity of target cells. With immature cells the haemin-induced stimulation starts after the first hour and continues to increase up to 20 h of culture. Erythropoietin but not haemin can stimulate the basal activity of adenylate cyclase in an in vitro assay containing plasma membranes of immature erythroid cells. The degree of activation depends on the concentration of erythropoietin and is maximal with 0.2-0.5 U/ml hormone (5-12 nM). In the presence of guanine nucleotides the activation of adenylate cyclase by erythropoietin is increased further but the effect is not additive. With respect to the basal and the guanine-nucleotide-stimulated activities of adenylate cyclase erythropoietin acts differently from the beta-agonist l-isoprenaline. The in vitro effect of erythropoietin is abolished by the beta-thio analogue of GDP, GDP[beta S], and extensive washing of membranes makes hormone action GTP-dependent. The stimulation of adenylate cyclase by the addition of erythropoietin to the reaction mixture is inversely related to the extent of previous hormonal stimulation of the cells from which the membranes were prepared. This loss of hormonal responsiveness is due to desensitization or receptor down-regulation and persists for up to 20 h. We conclude that in immature erythroblasts erythropoietin acts via a receptor and a guanine nucleotide-binding protein with high affinity for GTP (EC50 less than 10 nM), whereas haemin appears to activate adenylate cyclase indirectly, as a consequence of progressive perturbations of the plasma membrane.
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PMID:Stimulation of the adenylate cyclase activity of rabbit bone marrow immature erythroblasts by erythropoietin and haemin. 395 92

Suspensions of reticulocyte-enriched red cells produce and extrude cyclic AMP in proportion to their reticulocyte content. When reticulocytes are treated with the beta-adrenergic agonist isoproterenol, up to 3.5 pmoles of cyclic AMP/min/mg protein appear in the extracellular medium. Extruded cyclic AMP can occur against apparent concentration gradients and is inhibited by agents (iodoacetate, dinitrophenol) that deplete cellular ATP, as well as by probenecid and prostaglandin A1. Extrusion of cyclic AMP depends on the availability of intracellular cyclic AMP but is not obligatorily coupled to adenylate cyclase activity: extrusion continues following termination of a pulse of stimulation and exhibits a temperature dependence that differs from that for cyclic AMP production in response to isoproterenol. Erythropoietin affects neither production nor extrusion of cyclic AMP by reticulocytes. In whole blood, cyclic AMP extruded by reticulocytes may be a significant source of plasma cyclic nucleotide.
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PMID:Export of cyclic AMP by mammalian reticulocytes. 626 Aug 42

Rauscher murine erythroleukemia cells, grown continuously in vitro, undergo erythroid differentiation in response to the hormone erythropoietin. Therefore, they serve as an important model system with which to examine critical biochemical aspects of this developmental process. Intact, uninduced Rauscher cells possess a functional beta-adrenergic receptor-adenylate cyclase complex. The adrenergic agonists, isoproterenol, epinephrine, and norepinephrine, exhibited activation constants (Kact) of 0.1, 0.5, and 20 mumol/L, respectively. Thus, the beta-receptor-cyclase complex of Rauscher cells is apparently one of the most sensitive of all erythroid cells reported thus far. The epinephrine-stimulated cyclic adenosine monophosphate (cAMP) response was inhibited by propranolol, alprenolol, and hydroxybenzylpindolol, with inhibition constants (KI) of 3.8, 2.2, and 0.1 nmol/L, respectively. Using [125I]-iodohydroxybenzylpindolol as ligand, uninduced Rauscher cells were shown to possess 1,100 receptors/cell, with an equilibrium dissociation constant (KD) of 400 pmol/L. Erythropoietin, but not dimethylsulfoxide, induction caused a specific increase in receptor density to 3,300/cell on differentiating Rauscher cells. This is the first demonstration of membrane receptor regulation by erythropoietin that may be important in the complex interplay of hormonal effects during erythropoiesis.
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PMID:The beta-adrenergic receptor adenylate cyclase complex of Rauscher murine erythroleukemia cells and its response to erythropoietin-induced differentiation. 632 80