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)

We have previously reported that anti-fucosyl GM1 ganglioside antibody partially suppresses cAMP production in FRTL-5 rat thyroid cells not via the TSH receptor but via guanine nucleotide-binding protein indirectly. In order to clarify further the mechanism of the antibody action, we studied the relationship with alpha 2- and beta-adrenergic and adenosine A1 receptors. FRTL-5 cells did not bind [3H]clonidine, suggesting the lack of alpha 2-adrenergic receptor or at least abnormality of its binding domain. On the other hand, the cells specifically bound [125I]iodocyanopindolol, but isoproterenol failed to affect the basal and TSH-stimulated cAMP production indicating the lack of coupling with adenylate cyclase. The inhibition of cAMP production induced by anti-fucosyl GM1 antibody was not altered by adrenergic agents. [125I]hydroxyphenylisopropyl adenosine binding was observed in FRTL-5 cells but was not displaced by the antibody. These results lead to conclusions that FRTL-5 cells lack alpha 2-adrenergic receptor but have beta-adrenergic receptor which lacks coupling with adenylate cyclase and have adenosine A1 receptor, and that the adrenergic receptors and adenosine A1 receptor are not the site of action of anti-fucosyl GM1 antibody.
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PMID:Alpha 2- and beta-adrenergic receptors and adenosine A1 receptor of FRTL-5 rat thyroid cells in relation to fucosyl GM1 ganglioside. 254 96

We investigated regulation of cardiac adenylate cyclase in 29-d-old BIO 14.6 Syrian hamsters, which inherit cardiomyopathy as an autosomal recessive trait. Pharmacologic stimulation of adenylate cyclase in cardiac membranes with isoproterenol, fluoride ion, guanine nucleotide, forskolin, and manganous ion indicated that there was defective coupling of the guanine nucleotide-binding protein that stimulates adenylate cyclase (Gs) to adenylate cyclase. Cyc complementation assays revealed congruent to 50% less Gs activity in cardiac and skeletal muscle from cardiomyopathic hamsters. Despite this decrease in functional Gs, there were no changes in immunologic levels of the alpha-subunit of Gs (alpha Gs) or in levels of mRNA encoding alpha Gs. The defect in Gs bioactivity was limited to cardiac and skeletal muscle, occurred only in animals homozygous for the dystrophic trait, and was demonstrable before any cardiac abnormalities were evident on light microscopy. By contrast, cardiac levels of beta-adrenergic receptors were not different in cardiac membranes from BIO 14.6 hamsters. We conclude that a functional defect in alpha Gs may contribute to a contractile abnormalities in the cardiomyopathic BIO 14.6 hamster. However, the etiology of the alpha Gs defect remains obscure.
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PMID:Decreased bioactivity of the guanine nucleotide-binding protein that stimulates adenylate cyclase in hearts from cardiomyopathic Syrian hamsters. 254 25

Patients with pseudohypoparathyroidism type Ia have resistance to multiple hormones because of deficient activity of the stimulatory guanine nucleotide-binding protein (Gs) that couples membrane receptors to activation of adenylate cyclase. However, in a subset of patients with pseudohypoparathyroidism who have resistance to multiple hormones yet possess normal erythrocyte membrane Gs activity, the biochemical abnormality responsible for hormone resistance has remained undefined. Cultured skin fibroblasts were derived from a patient with this atypical form of pseudohypoparathyroidism. In the patient's fibroblast membranes, adenylate cyclase stimulation mediated by Gs after fluoride ion treatment produced only 52% of normal activity, yet fibroblast membrane Gs activity measured by cyc- complementation was normal. Activation of the catalytic unit of adenylate cyclase with manganese produced 49% of normal activity; manganese plus forskolin produced 54% of normal adenylate cyclase activity. beta-Adrenergic receptor coupling to Gs and phosphodiesterase activity were normal. A defect in the catalytic unit of adenylate cyclase can account for these results and may be a mechanism for clinical resistance to multiple hormones that act through adenylate cyclase.
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PMID:New form of pseudohypoparathyroidism with abnormal catalytic adenylate cyclase. 254 94

Forskolin increased intracellular cyclic AMP and augmented cyclic AMP formation by prostaglandin E1 (PGE1) in normal rat hepatocytes and ascites hepatoma AH66 cells. However, in AH66F cells which were derived from the AH66 cell line, the diterpene only slightly increased the cyclic AMP level, and dose-dependently inhibited the accumulation caused by PGE1. Forskolin dose-dependently activated adenylate cyclase in these membranes, and the magnitude of activation by forskolin was largest in the following order: hepatocytes, AH66 cells, and AH66F cells. This difference may be based on the number of forskolin-binding sites. The binding affinity of forskolin for each cell membrane was similar. The number and affinity of forskolin-binding sites in these cells were not influenced by 5'-guanylylimidodiphosphate [Gpp(NH)p]. In hepatocytes and AH66 cells, forskolin and other adenylate cyclase activators such as PGE1, GTP, Gpp(NH)p, F-, and Mn2+ synergistically increased the enzyme activity. In AH66F cells, the forskolin-stimulated activity was hardly influenced by the GTP analog, and forskolin diminished the activities induced by the GTP analog in a manner similar to that of diterpene alone. Forskolin (10 microM) also significantly inhibited the activities induced by PGE1, GTP, and F-. The effect of forskolin with Mn2+ was additive in AH66F cells. The data suggest that forskolin promotes the interaction between the stimulatory guanine nucleotide-binding protein and the catalytic unit in the membrane of normal hepatocytes and AH66 cells, but it interferes with the coupling in AH66F cells.
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PMID:Forskolin inhibits the Gs-stimulated adenylate cyclase in rat ascites hepatoma AH66F cells. 255 5

The stimulatory guanine nucleotide-binding protein (Gs), which links cell-surface receptors to second-messenger effector systems, is assumed to be confined to plasma membranes. In the current studies we tested whether Gs redistributes within cells by treating S49 lymphoma cells with the beta-adrenergic agonist isoproterenol, then separating cytosol and crude membrane fractions (defined as pellet and supernatant, respectively, after centrifugation for 1 hr at 150,000 x g), and assaying fractions for the alpha subunit of Gs (alpha s) using a competitive ELISA and reconstitution techniques. Under basal conditions, a small (10%) pool of alpha s was identified in supernatant fractions of S49 cells. The size of this pool decreased in the first 15 min after agonist treatment of cells. This decrease was blocked by a beta-adrenergic receptor antagonist and did not occur in an S49 variant, UNC, which lacks functional interaction between receptors and Gs. The size of the alpha s pool in supernatant fractions increased to almost 50% of total cellular alpha s during a 1-hr incubation of cells with isoproterenol. Before isoproterenol treatment only the competitive ELISA was sensitive enough to detect cytosolic alpha s, whereas at later time points (greater than or equal to 30 min) the presence of alpha s in the cytosol was confirmed by both immunoblotting and by reconstitution of adenylyl cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] in Gs-deficient membranes derived from cyc-S49 cells. In contrast to membrane alpha s, cytosolic alpha s did not require activation (e.g., by AlF4-) in the reconstitution assay to stimulate adenylyl cyclase. Use of an antibody that selectively recognizes monomeric dissociated alpha s, but not heterotrimeric alpha s, indicated that cytosolic alpha s is monomeric. These data indicate that alpha s is not exclusively localized to the plasma membrane and that agonist treatment redistributes this protein within target cells.
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PMID:Stimulation of beta-adrenergic receptors of S49 lymphoma cells redistributes the alpha subunit of the stimulatory G protein between cytosol and membranes. 255 94

It is well known that myocardial responsiveness to catecholamines declines with age besides the elevation of plasma catecholamine concentration. Moreover, age-related alterations in beta-adrenergic receptor-adenylate cyclase system are thought to be a mechanism of the decreased responsiveness. In this study, using Wistar rat myocardium (3, 26, 52, 104 weeks old), alterations in beta-adrenergic receptor (Rs), stimulatory guanine nucleotide-binding protein (Gs), inhibitory guanine nucleotide-binding protein (Gi), and catalytic unit of adenylate cyclase system (C) were investigated. All components consisting the system altered with development and aging: 1) The density of Rs (Bmax) decreased with development. On the other hand, the dissociation constant of Rs (Kd) to Iodocyanopindolol did not change. 2) Forskolin-stimulated activity of C decreased significantly between 3 and 26, between 52 and 104 weeks old. 3) Activity of Gs decreased with development, and did not with aging. In addition, SDS-PAGE and autoradiography revealed that the major alpha-subunits of Gs ADP-ribosylated by cholera toxin changed from peptides of Mr = 45,000 and 47,000 to peptide of Mr = 52,000 with aging. 4) The function of G1 declined with aging. And it was confirmed in this study that function of G1 declined with aging. And it was confirmed in this study that alpha-subunit of Gi ADP -ribosylated by IAP (islet-activating protein) decreased with development and aging.
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PMID:[Development- and age-related alterations of beta-adrenergic receptor--adenylate cyclase system in rat myocardium]. 282 22

The neuropeptide bombesin acts on a variety of target cells to stimulate the processes of secretion and cell proliferation. In this study we determined whether bombesin receptors interact with known guanine nucleotide-binding proteins in four different cell types: GH4C1 pituitary cells, HIT pancreatic islet cells, Swiss 3T3 fibroblasts, and rat brain tissue. Maximal concentrations of nonhydrolyzable GTP analogs decreased agonist binding to bombesin receptors in membranes from all four sources. In GH4C1 and HIT cell membranes GTP analogs inhibited bombesin receptor binding with IC50 values of about 0.1 microM, whereas GDP analogs were approximately 10-fold less potent. In contrast, GMP and the nonhydrolyzable ATP analog adenylyl-imidodiphosphate had no effect at 100 microM. Equilibrium binding experiments in GH4C1 and HIT cell membranes indicated a single class of binding sites with a dissociation constant (Kd) for [125I-Tyr4]bombesin of 24.4 +/- 7.0 pM and a binding capacity of 176 +/- 15 fmol/mg protein. Guanine nucleotides decreased the apparent affinity of the receptors without significantly changing receptor number. Consistent with this observation, guanine nucleotides also increased the rate of ligand dissociation. Pretreatment of GH4C1 or HIT cells with either pertussis toxin (100 ng/ml) or cholera toxin (500 ng/ml) for 18 h did not affect agonist binding to membrane bombesin receptors, its regulation by guanine nucleotides, or bombesin stimulation of hormone release. Although pertussis toxin pretreatment has been reported to block bombesin stimulation of DNA synthesis in Swiss 3T3 cells, it did not alter the binding properties of bombesin receptors in Swiss 3T3 membranes or inhibit the rapid increase in intracellular [Ca2+] produced by bombesin in these cells. In summary, our results indicate that the bombesin receptor interacts with a guanine nucleotide-binding protein which exhibits a different toxin sensitivity from those which regulate adenylate cyclase as well as those which couple some receptors to phospholipases.
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PMID:The bombesin receptor is coupled to a guanine nucleotide-binding protein which is insensitive to pertussis and cholera toxins. 283 Feb 64

We have investigated the mechanisms underlying prostaglandin inhibition of histamine-stimulated parietal cell function. Enzyme-dispersed canine parietal cells were enriched by elutriation. The accumulation of the weak base [14C]aminopyrine was used as an index of parietal cell function and cyclic adenosine monophosphate content was measured by radioimmunoassay. Step density gradients of the elutriator-enriched parietal cell fractions indicated that parietal cells accounted for the histamine stimulation of cyclic adenosine monophosphate production and inhibition by the prostaglandin E analogue Enprostil. Pertussis toxin adenosine diphosphate-ribosylates a subunit with a molecular weight of 41,000, thereby inactivating the inhibitory guanine nucleotide-binding protein of adenylate cyclase. Pertussis toxin treatment of parietal cells in overnight suspension culture was used to determine if inhibitory guanosine triphosphate-binding protein mediated prostanoid inhibition. In control cultured cells, prostaglandin E2 and Enprostil markedly inhibited forskolin- and histamine-stimulated aminopyrine accumulation. In parietal cells treated with pertussis toxin (300 ng/ml) for 18 h, stimulation of parietal cell function by histamine, isobutylmethylxanthine, and forskolin was unaltered compared with control cells, whereas prostaglandin E2 and Enprostil inhibition was markedly reduced. In pertussis toxin-treated cells, histamine-stimulated cyclic adenosine monophosphate generation was unaltered, whereas Enprostil inhibition of histamine-stimulated cyclic adenosine monophosphate production was markedly reduced. Pertussis toxin treatment of membranes from control, but not from pertussis toxin-treated, cells induced the [32P]adenosine diphosphate-ribosylation of a membrane protein with a molecular weight of 41,000, presumably the alpha-subunit of inhibitory guanosine triphosphate-binding protein. We conclude that prostanoids inhibit parietal cell function by receptor-mediated interaction with the inhibitory guanine nucleotide-binding protein of adenylate cyclase.
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PMID:Prostanoid inhibition of canine parietal cells: mediation by the inhibitory guanosine triphosphate-binding protein of adenylate cyclase. 283 42

We studied the molecular mechanisms of the abnormal response of the beta-adrenergic receptor-adenylate cyclase system in the myocardium of spontaneously hypertensive rats (SHR) by ADP-ribosylation catalyzed by cholera toxin and pertussis toxin, by reconstitutive assay of cardiac membranes with the human platelet membranes, and by immunostaining with polyclonal antibody against beta gamma-subunits of guanine nucleotide-binding proteins. The maximal activity of the enzyme stimulated by forskolin was higher in SHR than in control Wistar Kyoto (WKY) rats. However, the activity stimulated by isoproterenol, glucagon, histamine was similar for SHR and control rats. Moreover, the activity stimulated by PGE1 was lower in SHR than in control rats. The activity of the stimulatory guanine nucleotide-binding protein (Gs) of cholate extracted cardiac membranes from SHR was significantly lower than that from control rats. There were no strain differences in (1) number and affinity of beta-adrenergic receptors, (2) the function and amount of the inhibitory guanine nucleotide-binding protein (Gi), (3) substrates for cholera toxin catalyzed ADP-ribosylation, and (4) the amount of beta gamma-subunits of Gs and Gi. Thus, there is an abnormal signal transduction in beta-adrenergic receptor coupled adenylate cyclase system in SHR due to a reduction in the activity of the alpha-subunits of Gs.
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PMID:[Abnormalities in the beta-adrenergic receptor-adenylate cyclase system in the ventricular myocardium of spontaneously hypertensive rats]. 283 80

The rat Sertoli cell in culture expresses A1 inhibitory adenosine receptors. In this study, we have used pertussis toxin as a tool to characterize the mechanism of action of adenosine on these cells. Cells were preincubated for 18-24 h with pertussis toxin, and the responses to FSH and to the adenosine analog phenylisopropyladenosine (PIA) were measured by assaying cAMP accumulation. The effect of toxin on adenosine receptors was also evaluated by measuring binding of the adenosine agonist cyclohexyladenosine (CHA). The total number of specific CHA-binding sites was reduced 60-70% in membranes prepared from cells cultured for 24 h in the presence of pertussis toxin; the binding sites remaining after treatment displayed no apparent change in affinity for [3H]CHA. The effect of guanine nucleotides on CHA binding was also reduced after toxin pretreatment, but not abolished. PIA inhibited FSH-stimulated cAMP accumulation by 70-80%. Maximal inhibition was observed at a concentration of 10 nM PIA, and the ED50 of the dose-response curve was 1 nM. Pretreatment of the Sertoli cell with pertussis toxin completely blocked the PIA inhibition. The pertussis toxin effect was time and dose dependent. Reversal of the inhibition was observed after 6 h of treatment with a maximal dose of toxin (100 ng/ml). The dose of toxin producing a half-maximal effect was 10-30 ng/ml. In addition to this blockade of purine nucleotide inhibitory effects, exposure of the Sertoli cell to pertussis toxin concentrations ranging from 1-400 ng/ml consistently led to a potentiation of the FSH response measured as cAMP accumulation. In cell-free preparations (crude particulate fraction of the Sertoli cells, or sucrose gradient-purified plasma membranes), pertussis toxin catalyzed the incorporation of [32P]ADP ribose into a polypeptide with a molecular mass of 40-41 K. This peptide had electrophoretic mobility similar to that of a partially purified guanine nucleotide-binding protein (Gi). These data indicate that adenosine A1 inhibitory receptors are coupled to an inhibitory component (Gi) of adenylate cyclase. In the Sertoli cell, inhibitory and stimulatory signals interact in a bimodal regulation of adenylate cyclase and intracellular cAMP.
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PMID:Adenosine inhibition of the hormonal response in the Sertoli cell is reversed by pertussis toxin. 283 71


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