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)

Bovine brain contains a heat-labile, 80,000-dalton calmodulin-binding protein (CaM-BP80) which inhibits the calmodulin-dependent activities of cyclic 3',5'-nucleotide phosphodiesterase, adenylate cyclase, and Ca2+-ATPase in vitro. CaM-BP80 is composed of two polypeptides (60,000 and 18,500 daltons) present in a 1:1 ratio. An antibody directed against CaM-BP80 was raised in rabbits, and a radioimmunoassay was developed, having a sensitivity of 60 fmol of CaM-BP80. Using the radioimmunoassay, we determined the levels of CaM-BP80 in various bovine tissues. The protein was found primarily in the brain, present in particularly high levels in the neostriatum. These results, together with immunohistochemical localization of CaM-BP80 at the postsynaptic densities and the microtubules of postsynaptic dendrites [Wood, J.G., Wallace, R., Whitaker, J., & Cheung, W.Y. (1980) J. Cell Biol. 84, 66-76], suggest that the protein may have a role in the cerebrum at the site of neurotransmitter action and at the level of microtubular function.
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PMID:High levels of a heat-labile calmodulin-binding protein (CaM-BP80) in bovine neostriatum. 624 35

The isoform of protein kinase C responsible for the inhibition of histamine-stimulated adenylate cyclase by the phorbol ester, 12-O-tetradecanoylphorbol 13-acetate (TPA), has been investigated in a particulate fraction prepared from the human gastric cancer cell line HGT-1. The alpha and epsilon isoforms of protein kinase C were detected in HGT-1 cells and in a 40,000 x g particulate fraction by immunoblotting procedures. The inhibitory effect of TPA on histamine-stimulated adenylate cyclase was enhanced by the presence of Ca2+, but decreased in a concentration-dependent manner by anti-peptide antibody to protein kinase C alpha, but not to protein kinase C epsilon. Addition of Ca2+ and TPA to the 40,000 x g particulate fraction stimulated the phosphorylation of the protein kinase C substrate myelin basic peptide 4-14. Protein kinase C alpha is probably the isoform responsible for inhibition of histamine-stimulated adenylate cyclase in HGT-1 cells.
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PMID:The alpha isoform of protein kinase C inhibits histamine-stimulated adenylate cyclase activity in a particulate fraction of the human gastric cancer cell line HGT-1. 754 78

We examined a series of 2-aminochromone analogs typified by U-84569 [8-methyl-2-(4-morpholinyl)-7-(1-naphthylenylmethoxy)-4H-1- benzopyran-4-one] as potential antithrombotic agents. U-84569 proved to be a potent inhibitor of human platelet aggregation regardless of the agonist used. Subsequent experiments showed that U-84569 increased platelet cyclic AMP (cAMP) levels in intact cells, but U-84569 did not directly stimulate adenylate cyclase. Our experiments showed that U-84569 was a potent inhibitor of the low Km cAMP-dependent phosphodiesterase with an IC50 of 300 nM in platelet cytosol. Isobutylmethylxanthine had an IC50 of 10 microM in the same system. Although U-84569 elevated cAMP by inhibiting cAMP metabolism, we were interested in the mechanism by which cAMP blocked aggregation. Our first experiments showed that U-84569 concentration-dependently blocked agonist-stimulated, but not phorbol myristate acetate-dependent, phosphorylation of the 47 kDa protein kinase C substrate in platelets. These data suggested that U-84569 could interrupt receptor-mediated signal transduction. In support of this hypothesis, U-84569 proved to be a potent inhibitor of thrombin-stimulated inositol phosphate synthesis, diacylglycerol formation and Ca++ mobilization in intact cells. These data indicate that agonist-stimulated phospholipase C activity was reduced in U-84569-treated cells. There was no direct influence of U-84569 on either basal or thrombin-stimulated phospholipase C activity in broken cells, suggesting that U-84569 (by inhibiting phosphodiesterase and elevating cAMP), indirectly blocked receptor-mediated phospholipase C activation and aggregation in platelets. The 2-aminochromones represent a new class of potent antithrombotic agents.
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PMID:2-Aminochromones block human platelet aggregation by inhibiting cyclic AMP-dependent phosphodiesterase leading to reduced platelet phospholipase C activity. 768 15

The interaction between corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) is important in the regulation of adrenocorticotropin (ACTH) release from the anterior pituitary (AP). CRF exerts its effect on the AP by activating the adenylate cyclase (AC) complex whereas AVP increases the turnover of phosphatidylinositol. In the rat and in man, CRF is the most potent ACTH secretagogue whereas AVP alone is only a weak agonist. Since recent studies in the sheep indicate a reversal of this order of potency, these studies were undertaken to test the hypothesis that a functional alteration of the AC in the ovine corticotrope might limit the ability of CRF to release ACTH from these cells. When rat AP cells were incubated with CRF, a dose-dependent increase in AC activity was observed. This effect was potentiated either by AVP or PMA, although neither agent alone altered AC activity. In contrast, CRF alone, or in combination with AVP or PMA, did not increase AC activity in ovine AP cells. Both cholera toxin (CT) and pertussis toxin (PT) caused a dose-dependent release of ACTH from rat and ovine AP cells, but the amount of ACTH released from the ovine AP cells by both agents was relatively reduced. In the ovine cells, however, AVP acted synergistically with CT or PT to markedly increase the release of ACTH to levels which approached those obtained when the rat AP cells were exposed to CT or PT alone. Forskolin increased AC activity in AP cells of both species, but to a much lower extent in ovine cells than in the rat cells. However, when the ovine cells were exposed to AVP, the AC response to forskolin became similar to the response observed in the rat cells when incubated with forskolin alone. Forskolin also released significantly less ACTH from the ovine AP cells, but AVP also acted synergistically with forskolin to greatly enhance the amount of ACTH released from these cells. Finally, 8-bromo-cyclic AMP produced a similar release of ACTH from both ovine and rat AP cells. We conclude that: (1) the decreased ability of CRF to increase ACTH release from the ovine AP reflects a net decrease in AC activity and cannot be ascribed to an ovine corticotropic resistance to cAMP; (2) the decreased activity of the ovine corticotropic AC complex may in turn reflect functional alterations at the level of both the G proteins and the catalytic subunit; (3) since AVP causes protein kinase C substrate phosphorylation in the ovine AP, AVP may increase AC activity in this tissue by phosphorylating the G proteins and/or the catalytic subunit.
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PMID:A comparative study of the role of adenylate cyclase in the release of adrenocorticotropin from the ovine and rat anterior pituitary. 939 50

Neurogranin (Ng) is a newly discovered brain-specific protein composed of 78 amino acid residues, which mainly located postsynaptically in the cerebral cortex, hippocampus and olfactory bulb in adult human or animals. As a member of calpacitin family, Ng is a protein kinase C (PKC) substrate and calmodulin (CaM) reservoir. In the physiological conditions, Ng forms a complex with CaM, and its CaM-binding affinity was modulated by phosphorylation, oxidation and glutathiolation under the activation of PKC or oxidant stress, which may be involved in the regulation of CaM and CaM-activated proteins, such as CaM-dependent nitric oxide synthase (NOS), CaM-dependent protein kinase II (CaMKII) and CaM-dependent adenylate cyclase (AC). Since most of CaM-activated proteins were involved in long-term potentiation (LTP) and long-term depression (LTD), and the timing pattern of Ng gene expression and protein synthesis are coincidence with synaptogenesis and development, it is suggested that Ng may play an important role in learning, memory and neuroplasticity. In addition, it was found that the changes of Ng expression might associate with certain cerebral pathophysiologic disorders, such as hypothyroidism, sleep-deprivation, brain aging and cerebral hypoxic preconditioning.
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PMID:[Neurogranin: a brain-specific protein]. 1288 41

Neurogranin/RC3 (Ng/rodent cortex-enriched mRNA clone #3), a postsynaptic neuronal protein kinase C (PKC) substrate, binds calmodulin (CaM) at low Ca(2+) levels. Neurotransmitters triggering influx calcium induce neurogranin phosphorylation by PKC in physiological or pathophysiological conditions. Phosphorylated Ng reduces the affinity of Ng to bind CaM, which may affect the activities of calmodulin-dependent downstream enzymes, such as nitric oxide synthase (NOS), CaM-dependent protein kinase II (CaMKII) and adenylate cyclase (AC). These protein enzymes have been reported to play key roles in the development of ischemic/hypoxic preconditioning (I/HPC). We previously demonstrated that activation of cPKCbetaII and gamma isoforms may be involved in the early phase of cerebral hypoxic preconditioning. However, as a substrate of PKC, the role of Ng in the onset of cerebral hypoxic preconditioning is unknown. In this study, we examined the effects of repetitive hypoxic exposure on the status of Ng phosphorylation in the cortex and hippocampus of mice. Using Western blot analysis, we found that the levels of Ng phosphorylation in the cortex and hippocampus of the hypoxic group of mice increased significantly from that of the normoxic group (p<0.05). These results suggest that neurogranin protein may be involved in the development of cerebral hypoxic preconditioning.
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PMID:Increased phosphorylation of neurogranin in the brain of hypoxic preconditioned mice. 1618 46