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)

To assess the effect of fetal hypothyroidism during late gestation on postnatal cardiovascular responsiveness, we measured heart rate and cardiac output responses to isoproterenol in newborn lambs. To evaluate the effect of such altered thyroid status on the development of beta-adrenergic signaling cascade, we measured myocardial beta-adrenergic receptor concentration and affinity, guanine nucleotide regulatory protein density, and adenylyl cyclase responsiveness. Twenty fetal lambs underwent either thyroidectomy and line placement or line placement alone at 128-130 d gestation. Five thyroidectomized and six control newborns were treated with isoproterenol, five thyroidectomized and four control newborns were killed upon delivery and tissue was obtained for biochemical studies, and four additional animals were delivered and killed at 126 d gestation and tissue was obtained for receptor analysis. Of the newborns treated with isoproterenol, the thyroidectomized lambs showed lower increase in heart rate and cardiac output compared with euthyroid newborns. Compared with the myocardium of normal newborns of similar gestation, the myocardium of the newborns who underwent fetal thyroidectomy failed to show the normal increase in beta-adrenoceptors accompanied by reduction in beta-adrenergic-stimulated adenylate cyclase activity. These results suggest that near term, the normal development of ovine fetus myocardial beta-adrenergic receptor is affected by thyroid hormones.
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PMID:Effects of thyroid hormone on myocardial adrenergic beta-receptor responsiveness and function during late gestation. 131 39

This study was conducted in human subjects and in baboons to assess elements of the beta-adrenergic receptor complex in vivo and in vitro following cardiac transplantation. In human subjects, the concentration at which administered isoproterenol increased heart rate by 25 beats per min was within the normal range (mean, 3.2 +/- 0.4 micrograms). Myocardial biopsies and lymphocytes were obtained from 14 transplant recipients undergoing routine right heart catheterization. The stimulatory guanine nucleotide regulatory protein, Gs, was significantly greater in the lymphocyte than in right ventricular myocardium (5.8 +/- 1.7 vs. 2.0 +/- 0.5 relative to standard rat heart membrane preparation, P less than 0.05). In contrast, Gi was significantly greater in the myocardium than in the lymphocyte (4.2 +/- 1.3 vs. 1.1 +/- 0.3, P less than 0.025). There was no correlation between lymphocyte and cardiac G protein determinations. In the autotransplanted baboon heart, beta-receptors were increased (73 +/- 4 vs. 36 +/- 10 fmol/mg, P less than 0.05). Gs was not significantly different in denervated myocardial tissue vs. control cardiac tissue (1.1 +/- 0.2 vs. 0.8 +/- 0.2, P greater than 0.05). However, the inhibitory G protein, Gi, was significantly greater in transplanted animals (0.4 +/- 0.1 vs. 0.2 +/- 0.04, P less than 0.05). Relative enrichment of a Gi-like protein in the autotransplanted baboon heart was associated with a non-statistically significant trend towards a uniform reduction in basal and Gs-mediated adrenergic effects on adenylate cyclase activity. Despite the lack of biochemical evidence of enhanced beta-adrenergic receptor-mediated adenylate cyclase coupling, denervation in the autotransplanted baboon was associated with in vitro evidence of chronotropic and inotropic supersensitivity to isoproterenol. The results call into question the notion of adrenergic hypersensitivity in human subjects following cardiac transplantation, indicate the potential role for guanine nucleotide regulatory proteins in mediating responses of the denervated heart, and distinguish between several characteristics of the chronically denervated, transplanted human heart compared with the acutely auto-denervated of the baboon heart.
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PMID:Beta-adrenergic receptor sensitivity and guanine nucleotide regulatory proteins in transplanted human hearts and autotransplanted baboons. 166 Oct 39

In isolated and enriched guinea-pig gastric mucous cells the effects of carbachol, prostaglandin E2 (PG E2), prostaglandin F2 alpha (PG F2 alpha) and histamine on adenylate cyclase (AC) and cytosolic free Ca2+ were investigated, in order to study the biochemical mechanisms involved in secretagogue-mediated mucus release. Histamine and both prostaglandins stimulated AC in partially purified membranes of mucous cells. Histamine was most efficacious, followed by PG E2 and PG F2 alpha. The histamine effect was blocked by the H2-receptor antagonist ranitidine, but not by the H1-receptor antagonist mepyramine. Carbachol raised the resting [Ca2+]i in mucous cells from 120 to 306 nM. This carbachol effect was blocked by atropine. Histamine and PG E2 stimulation of AC was inhibited in a concentration-dependent manner by Ca2+ (IC50:31 microM). In the presence of TPA and phosphatidylserine, conditions which activate protein kinase C, the inhibitory action of Ca2+ on AC was significantly increased. These data indicate that there exists a negative feedback control mechanism between protein kinase C and histamine/prostaglandin E2-induced AC activation. From the finding that TPA and phosphatidylserine increased the inhibitory action of Ca2+ on cholera toxin-, but not on forskolin-stimulated AC we assume that the point, where protein kinase C exerts its inhibitory effect at the AC, is the guanine nucleotide regulatory protein.
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PMID:Signal transduction pathway in gastric mucous cells. 182 37

The relationship of adenotin, a low-affinity adenosine-binding protein, to adenosine receptors was examined in two human tissues and two mammalian cultured cell lines. An adenosine A2 receptor exists in the membranes from platelets, PC-12 cells, and JAR cells as shown by a stimulation of adenylate cyclase related to 5'-N-ethylcarboxamidoadenosine (NECA) or a NECA-related increase in intracellular cAMP levels. In contrast, binding studies with tritiated NECA revealed typical adenotin-like low-affinity binding sites on the membranes from the sources studied with agonist potencies as follows: NECA greater than 2-chloroadenosine greater than R-PIA. No evidence was found of coupling to a guanine nucleotide regulatory protein. Solubilization of platelet and placental membranes and precipitation with polyethylene glycol separated adenotin or the adenotin-like protein from a second adenosine binding site in each tissue. The pharmacologic properties of the precipitated binding sites were compatible with an adenosine A2 receptor in platelets and an adenosine A1 receptor in placenta. Our observations indicate that adenotin-like proteins exist outside the placenta. In addition, adenotin and adenotin-like proteins coexist with the adenosine A1 or A2 receptor in a number of cells and tissues and do not couple to a guanine nucleotide regulatory protein and stimulate adenylate cyclase. Therefore, adenotin is pharmacologically distinct from adenosine receptors, and its function remains to be discovered.
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PMID:Adenotin and adenotin-like proteins coexist with adenosine receptors in mammalian tissues. 184 70

We have previously shown that FSH receptors are physically and functionally associated with a guanine nucleotide regulatory protein (Gs) in membranes of calf testis. Using N-ethylmaleimide (NEM), forskolin, and cholera toxin as probes, we have investigated the role of low and high affinity GTP-binding sites of stimulatory guanine nucleotide-binding protein of adenylate cyclase (Gs) in the activation of adenylate cyclase. When calf testis membranes were exposed to NEM (1 mM), FSH binding to receptors was slightly (30%) decreased, but the receptors showed continued sensitivity to GTP, resulting in a further decrease in [125I]human FSH binding to receptors. Pretreatment of membranes with NEM (up to 20 microM) produced no effect on GTP-binding. A dose-dependent decrease in high affinity GTP-binding sites, however, was observed at higher (greater than 50 microM) NEM. Adenylate cyclase activity was reduced in response to GTP gamma S or NaF concomitant to a decrease in high affinity GTP-binding sites in membranes treated with 50-100 microM NEM, or completely abolished in membranes exposed to 300 microM NEM. Stimulation by forskolin indicated that the significant inhibition of adenylate cyclase activity occurring in membranes exposed to low NEM (50-100 microM) was not due to inactivation of catalytic unit of adenylate cyclase by NEM. Pretreatment of membranes with 100 micrograms/ml cholera toxin and NAD slightly (18%) reduced specific FSH binding but did not affect Gpp(NH)p-binding. However, adenylate cyclase stimulation by GTP plus FSH in these membranes was significantly enhanced. When membranes were treated with higher concentration of cholera toxin (250 micrograms/ml), the adenylate cyclase stimulation by GTP plus FSH was abolished due to uncoupling of FSH receptors from Gs and a significant decrease in high affinity GTP-binding sites. Our results suggest that high affinity GTP-binding sites of Gs coupled to FSH receptors are essential for FSH and guanine nucleotide activation of adenylate cyclase. The low affinity binding sites bind GTP and thereby regulate FSH binding but are not involved in the activation of adenylate cyclase.
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PMID:Differential roles of high and low affinity guanosine 5'-triphosphate binding sites in the regulation of follicle-stimulating hormone binding to receptor and signal transduction in bovine calf testis membranes. 189 82

Somatostatin was incubated in an adenylate cyclase assay of a particulate fraction of caudate-putamen tissue of the rat in order to examine the effect of the peptide on D-1 receptor coupled adenylate cyclase in vitro. Somatostatin was able to enhance cyclic AMP formation in the presence of guanylylimidodiphosphate and guanosine-triphosphate. In contrast to this, somatostatin inhibited both dopamine and forskolin-stimulated cyclic AMP accumulation. Pertussis toxin and cholera toxin also depressed forskolin-induced stimulation. Somatostatin was found to antagonize these inhibitory effects of pertussis toxin and cholera toxin. The results suggest that somatostatin acts through a stimulatory as well as an inhibitory guanine nucleotide regulatory protein subtype to affect dopaminergic adenylate cyclase activity.
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PMID:Somatostatin acts through G-proteins on dopaminergic adenylate cyclase in the caudate-putamen of the rat. 198 58

Binding of the catecholamine agonists epinephrine and norepinephrine to the beta-adrenergic receptor (BAR) rapidly activates adenylate cyclase via the stimulatory guanine nucleotide regulatory protein Gs, and results in rises in cellular levels of cAMP. However, continuous exposure to these agonists leads within minutes to a dampening of the enzymatic response. Both in vivo and in vitro studies have implicated agonist-induced phosphorylation of BAR in this process. These results include the isolation of a novel beta-adrenergic receptor kinase (BARK), which has been shown to preferentially phosphorylate receptors that are occupied by agonist when assessed in vitro. Recent studies in our laboratory have examined the desensitization process in intact cells to determine where on the receptor molecule functionally relevant phosphorylation occurs, and to identify the kinase(s) involved. In one set of studies, site-specific mutagenic techniques with the cloned gene for the human beta 2-adrenergic receptor were utilized to delete putative sites of phosphorylation by BARK and/or the cAMP-dependent protein kinase (PKA). Following expression of the mutated receptors in mammalian cells, the cells were challenged with different concentrations of agonist for 10-15 min and the functional and phosphorylation properties of the mutant receptors were then assessed. In another set of studies human A431 cells were permeabilized with low concentrations of digitonin and treated with selective inhibitors of both BARK and PKA. The cells were then exposed to desensitizing concentrations of agonist, and similar measurements performed. Taken together, the results from both sets of studies suggest that exposure of cells to low (nanomolar) concentrations of agonist leads to phosphorylation of the receptor on one or both consensus sites for PKA, and that the predominant effect of this phosphorylation on the adenylyl cyclase response is a loss in sensitivity of the receptor to further stimulation by the agonist. In contrast, exposure of cells to higher (micromolar) concentrations of agonist leads to BAR phosphorylation by both PKA and BARK, the latter on the carboxyl terminal region of the receptor. Phosphorylation of the receptor by both kinases appears to be required for the full desensitization effect seen with the high concentration of agonist, which includes both losses in sensitivity and in the maximal responsiveness of the adenylyl cyclase response upon subsequent challenge with the agonist. Such a dual kinase control of BAR phosphorylation may have important implications for understanding the regulation of desensitization under different physiological circumstances.
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PMID:Two kinases mediate agonist-dependent phosphorylation and desensitization of the beta 2-adrenergic receptor. 198 69

This study was aimed at investigating the effects of treatment with a lithium-imipramine combination on the activity of adenylate cyclase in membranes from the cerebral cortex of the rat. Treatment with (1) lithium for 2 weeks, yielding a level of lithium in serum of 0.54 +/- 0.12 mmol/l, (2) imipramine for 4 weeks (10 mg/kg i.p. twice per day) and (3) a combination of the two drugs reduced isoprenaline-induced stimulation of adenylate cyclase by GTP, with a greater decrement with the combined treatment. None of the treatments exerted any effect on the activity of the enzyme stimulated by GTP alone. Lithium ex vivo inhibited the calcium (Ca2+)- and Gpp(NH)p-stimulated activity of adenylate cyclase, but imipramine ex vivo did not affect the activity of adenylate cyclase, stimulated by these activators. The lithium-imipramine treatment reduced Ca2(+)- and Gpp(NH)p-stimulated activity of adenylate cyclase, but this was not different from that observed in the lithium-treated group. In conclusion, the beta-adrenoceptor-stimulated adenylate cyclase was affected markedly by administration of lithium and imipramine together. In contrast to lithium ex vivo, imipramine ex vivo did not impair the activity of either the guanine nucleotide regulatory protein or the catalytic subunit, since no change in activity was observed in the presence of beta,gamma-imidoguanosine-5' triphosphate (Gpp(NH)p) or Ca2+. Furthermore, lithium ex vivo exerted its post-receptor effects on the adenylate cyclase, independent of imipramine. The decrement in activity of beta-adrenergic adenylate cyclase, induced by administration of the two drugs together may partly be involved in the therapeutic action of the augmentation of antidepressants by lithium in refractory depression.
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PMID:Effects of treatment with a lithium-imipramine combination on components of adenylate cyclase in the cerebral cortex of the rat. 210 75

An antibody (RM) raised against the carboxyl-terminal decapeptide of the alpha subunit of the stimulatory guanine nucleotide regulatory protein (Gs alpha) has been used to study the interaction of Gs alpha with bovine brain adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1]. RM antibody immunoprecipitated about 60% of the solubilized adenylate cyclase preactivated with either GTP-gamma-S or AlF4-. In contrast, RM antibody immunoprecipitated about 5% of the adenylate cyclase not preactivated (control) and 15% of the adenylate cyclase pretreated with forskolin. Adenylate cyclase solubilized from control membranes or GTP-gamma-S preactivated membranes was partially purified by using forskolin-agarose affinity chromatography. The amount of Gs alpha protein in the partially purified preparations was determined by immunoblotting with RM antibody. There was 3-fold more Gs alpha detected in partially purified adenylate cyclase from preactivated membranes than in the partially purified adenylate cyclase from control membranes. Partially purified adenylate cyclase from preactivated membranes was immunoprecipitated with RM antibody and the amount of adenylate cyclase activity immunoprecipitated (65% of total) corresponded to the amount of Gs alpha protein immunoprecipitated. Only 15% of the partially purified adenylate cyclase from control membranes was immunoprecipitated. The presence of other G proteins in the partially purified preparations of adenylate cyclase was investigated by using specific antisera that detect Go alpha, Gi alpha, and G beta. The G beta protein was the only subunit detected in the partially purified preparations of adenylate cyclase and the amount of G beta was about the same in adenylate cyclase from preactivated membranes and from control membranes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Immunoprecipitation of adenylate cyclase with an antibody to a carboxyl-terminal peptide from Gs alpha. 212 72

Physiologic responses mediated by calcium-mobilizing receptors are initiated by the phospholipase C-catalyzed generation from phosphatidyl inositol (4,5)-bisphosphate of two intracellular second messengers: inositol (1,4,5)-trisphosphate, which induces the release of calcium from intracellular stores, and diacylglycerol, which stimulates protein kinase C activity. Recent studies illustrating guanine nucleotide dependence for hormonal stimulation of membrane phospholipase C suggest involvement of a guanine nucleotide regulatory protein (G protein) in phosphoinositide/Ca2+ signaling. Kinetic analysis indicates that the receptor-stimulated phospholipase C catalytic cycle expresses properties similar to those described in detail for receptor and G protein-regulated adenylate cyclase. However, the identity of the phospholipase C-associated G protein remains to be established, and available data suggest that different G proteins (at least two) may be involved in a tissue- and/or receptor-specific manner. The identity of the phospholipase C involved in the action of calcium-mobilizing hormones also has not been established. Multiple forms of membrane-associated and cytosolic phospholipase C enzymes have been described during the last few years, which increases the apparent complexity of the system. The identification and purification of the G protein(s) and the phospholipase C enzyme(s) of this important signaling system followed by unambiguous reconstitution of their physiologic activities represent major challenges in this field for the coming years.
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PMID:G protein-dependent regulation of phospholipase C by cell surface receptors. 215 58


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