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)

Cyclic AMP-dependent protein kinase (cAMP-PK) is a ubiquitous enzyme that, when activated by cAMP, is capable of phosphorylating a variety of intracellular proteins. The central postulate of cAMP-mediated hormone action is that hormones regulate intracellular cAMP concentration and cAMP-PK mediates the effects of this second messenger. Although this postulate accurately describes cAMP action in certain systems, it does not adequately provide for recent observations of the accumulation of cAMP and the activation of protein kinase without the anticipated effects on protein kinase's substrates. Both biochemical and cytochemical technics provide evidence that hormonally-specific regulation of cAMP action occurs and is important. Our thesis is that hormonal regulation of metabolic events via cAMP is localized intracellular phenomenon. We propose that occupation of some cell-surface hormone receptors leads to cAMP accumulation and the activation of protein kinase in subcellular compartments, with the consequent phosphorylation of specific, rather than all, substrates of protein kinase. circumstances potentially contributing to this specificity include: (a) physical and kinetic compartmentation of hormone-receptor-adenylate cyclase complexes non-randomly within the cell membrane; and, (b) a fixed spatial relationship of hormonally activated adenylate cyclase and specific intracellular regions by the participation of cytoskeletal proteins.
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PMID:Functional compartments in cyclic nucleotide action. 629 May 50

A model is proposed for the role of the kidney in the control of erythropoietin production in which the initial trigger is an oxygen deficit created by anemia, hypobaria or ischemia. It is postulated that hypoxia creates a decrease in the oxygen level in a critical renal sensor cell, perhaps in the glomerular tuft, which eventually leads to the production of prostacyclin. It is possible that the endothelial cell in the glomerular tuft responds to this oxygen deficit to produce prostacyclin to trigger erythropoietin production. Recent studies on prostaglandin synthesis by human isolated glomeruli indicate that the most abundant prostanoid synthesized by the glomerular tuft cells was 6-keto PGF1 alpha, a metabolite of prostacyclin (PGI2). PGI2 has also been reported to be produced by isolated vascular endothelial cells. The mechanism by which hypoxia may initiate the synthesis and/or release of prostaglandins and prostacyclin in the renal cell has not been elucidated. Significant to erythropoietin production is the production by hypoxia of prostacyclin which eventually leads to the production of the metabolite 6-keto PGE1. We further propose that 6-keto PGE1 is the prostanoid which activates a specific cell membrane adenylate cyclase, causing the conversion of ATP to cyclic AMP. This is a very critical step in that there must be a sufficient amount of ATP remaining to generate cyclic AMP in order for erythropoietin biosynthesis to occur with the reduced level of ATP which may have caused a perturbation of the cell membrane. The elevated cyclic AMP leads to the activation of protein kinases which are essential in phosphorylating the lysosomal hydrolases released by hypoxia into the cytosol of the cell and may be the precursors of erythropoietin. Neutral proteases and lysosomal hydrolases, documented triggers of erythropoietin production, have been demonstrated to be elevated in the kidney after hypoxia. The mechanism of labilization and release of these enzymes from the renal lysosomes has been postulated to be related to increases in cyclic GMP levels in a renal cell. Hypoxia causes the release of renal lysosomal hydrolases which then undergo phosphorylation through activation by protein kinases following prostanoid stimulation of renal adenylate cyclase to generate cyclic AMP, resulting in increased biosynthesis of erythropoietin.
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PMID:Prostanoid activation of erythropoiesis. 654 29

Incubation of S49 cell membranes at 0 degree C resulted in a loss of adenylate cyclase activity, but addition of ATP and ATP regenerating system prevented the decrease of the activity. A non-phosphorylating analogue of ATP, adenyl-5'-yl imidodiphosphate, was less effective than ATP. Treatment of solubilized adenylate cyclase with calf intestine alkaline phosphatase caused the decrease of the activity. Membranes from cyc- S49 mutant cells, which are devoid of guanine nucleotide-binding protein, yielded the same results as membranes from S49 cells, indicating that the catalytic component is involved in the alteration of the enzyme activity by these treatments. These results suggest that phosphorylation and dephosphorylation of the catalytic component may regulate adenylate cyclase activity.
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PMID:Alteration of adenylate cyclase activity by phosphorylation and dephosphorylation. 683 11

The effects of (-)-isoproterenol on adenylate cyclase activity were studied in rat cerebral cortical membranes prepared and assayed in the presence of calcium ions. In assays carried out in the presence of high Mg2+ concentrations (5-10 mM) and of Ca2+ in the micromolar range, addition of 1-100 micro M (-)-isoproterenol caused over 50% inhibition of adenylate cyclase activity. Since these conditions are optimal for supporting endogenous phosphorylative activity in synaptic membranes, we tested whether the observed effects are mediated by changes in the phosphorylation of specific proteins in these membranes. This was done by preincubation of lysed synaptosomes under phosphorylating conditions in the presence and absence of isoproterenol followed by extensive washes and analysis of cyclic AMP formation in resuspended membranes. Addition of (-)-isoproterenol to the preincubation resulted in a 30% decrease of adenylate cyclase activity in the reincubation. Inclusion of [gamma-32P]ATP in the preincubation and examination of the phosphorylation state of specific proteins in membranes entering the reincubation revealed that (-)-isoproterenol inhibited the phosphorylation of a specific protein band with apparent molecular weight of 47,000 (designated band F). These results support the hypothesis that alterations in membrane protein phosphorylation induced by neurotransmitters play a role in the regulation of adenylate cyclase activity.
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PMID:Protein phosphorylation mediates effects of isoproterenol on adenylate cyclase activity in rat cortical membranes. 730 Oct 43

1. Application of the phosphatase inhibitors okadaic acid (OA) and microcystin (MC) to frog cardiomyocytes caused large increases in L-type calcium current (ICa) in the absence of beta-adrenergic agonists. The increase occurred without effects on the peak current-voltage relation or voltage-dependent inactivation. OA and MC caused a decrease in amplitude of delayed rectifier current (IK), which is opposite to the increase produced by cAMP-dependent phosphorylation. The decrease occurred without effects on voltage-dependent activation or reversal potential. 2. Analysis of the dose-response relations for OA and MC on ventricular cell ICa were best fitted with a single-site relationship with a K1/2 of 1.58 microM and 0.81 microM, respectively. These data suggest the predominant form of phosphatase active on ICa in this cell type is produced by protein phosphatase 1. Inhibition of phosphatase 2B (calcineurin) was without appreciable effect. 3. Reducing intracellular ATP levels was without effect on basal ICa suggesting that calcium channels may not need to be phosphorylated to open. ATP depletion was able to block completely the ICa increase induced by OA or MC. This demonstrates that the effects of OA and MC on ICa are mediated by a phosphorylation reaction. In contrast, ATP depletion totally abolished IK, suggesting either a requirement for ATP or phosphorylation for basal function of the delayed rectifier channel. 4. Internal perfusion of a peptide inhibitor (PKI(5-22)) of protein kinase A (PK-A) was without effect on basal current levels of ICa or IK, suggesting that this kinase is not phosphorylating these channels under basal conditions. Furthermore, although PKI is capable of completely blocking the response of ICa to isoprenaline or forskolin, PKI does not affect the increase in ICa induced by MC or OA. Inhibition of adenylate cyclase with acetylcholine or inhibition of PK-A with adenosine cyclic 3',5'-(Rp)-phosphothioate (Rp-cAMPS) also had no effect on the response to OA or MC. 5. Application of beta-adrenergic agonist, forskolin or cAMP all produced additional increases in the presence of saturating doses of MC or OA. This supports the hypothesis that PK-A is not mediating the OA response and that phosphatase inhibition does not result in complete phosphorylation of PK-A sites. 6. To attempt to identify the protein kinase activity responsible for OA effects on ICa and IK, several types of protein kinase inhibitors were internally perfused.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Opposite effects of phosphatase inhibitors on L-type calcium and delayed rectifier currents in frog cardiac myocytes. 814 46

Norepinephrine and the beta-adrenergic receptor agonist, isoproterenol, have been shown to potentiate the amplitude of GABAA receptor-mediated whole-cell current responses in Purkinje cells acutely dissociated from the rat cerebellum. However, the steps leading from the activation of beta-adrenergic receptors to the modulation of GABAA receptor remain to be delineated. This study tested the hypothesis that a sequelae of intracellular intermediaries involving the cyclic AMP second messenger system serves as the subcellular link to promote this heteroreceptor interaction. Exposure to cholera toxin, but not to pertussis toxin, increased the amplitude of GABA-activated current responses in acutely dissociated Purkinje cells. Intracellular dialysis with guanosine 5'-O-(3-thiotriphosphate) also resulted in a time- and dose-dependent augmentation of the response to GABA. while guanosine 5'-O-(2-thiodiphosphate) blocked the norepinephrine-mediated facilitation. A positive modulation of the current response to GABA was observed following intracellular delivery of cyclic AMP or the catalytic subunit of the cyclic AMP-dependent protein kinase. Furthermore, the norepinephrine-induced potentiation of the GABA-activated current response was prevented in the presence of the Rp isomer of cyclic AMP, the regulatory subunit of cyclic AMP-dependent protein kinase and an inhibitor of cyclic AMP-dependent protein kinase. These findings led to the formulation of a working model in which activation of the beta-adrenergic receptor triggers a Gs-protein-mediated transduction cascade in cerebellar Purkinje cells which activates adenylate cyclase, resulting in a rise in intracellular levels of cyclic AMP, increased phosphorylating activity by cyclic AMP-dependent protein kinase and, ultimately, a potentiation of GABAA receptor function.
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PMID:Noradrenergic potentiation of cerebellar Purkinje cell responses to GABA: cyclic AMP as intracellular intermediary. 888 79

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

Beta-adrenergic agonists are well known to increase the activity of adenylate cyclase, yielding increases of the intracellular concentration of cAMP. It has been reported that activation of protein kinase C (PKC) by phorbol esters reduces the amplitude of isoproterenol-induced cAMP production in a 3T3-L1 cell line. In this study, we investigated whether PKC-alpha is involved in this process in murine Swiss 3T3 fibroblasts. A 20-mer phosphorothioate oligonucleotide designed to hybridize to the AUG initiation codon of the murine PKC-alpha mRNA, which contains 2'-O-methoxyethyl modifications incorporated into the 5' and 3' segments of the oligonucleotide, was used to assess the putative role of PKC-alpha in the beta-adrenergic receptor regulation. ISIS 14012 reduced PKC-alpha mRNA for over 72 hr after the initial treatment and the reduction was concentration dependent, whereas the mismatch control, ISIS 13818, had no effect. This depletion was found to be selective; ISIS 14012 had no effect on the mRNA expression of PKC-delta and PKC-zeta. ISIS 14012 reduced in a time and concentration-dependent fashion the levels of immunoreactive PKC-alpha protein by over 85% at 72 hr after treatment. Depletion of PKC-alpha inhibited the effect of isoproterenol-induced cAMP production by phorbol dibutyrate (PdBu). This finding is corroborated by the use of a nonspecific inhibitor of PKC, GF-109203x, which also prevented the effect of PdBu. Depletion of PKC-alpha by ISIS 14012 potentiated isoproterenol-induced cAMP production in cells untreated with PdBu. However, neither depletion of PKC-alpha nor PKC activation by a phorbol ester altered beta-adrenergic receptor affinity and density. PKC activation by PdBu did not alter forskolin-induced cAMP levels, but enhanced cAMP production by cholera toxin. PKC-alpha inhibition by ISIS 14012 had no effect on either cholera toxin-induced increases in cAMP or the acute effects of phorbol esters on cholera toxin in induction of cAMP. Thus, PKC-alpha appears to be involved in the regulation of beta-adrenergic receptor coupling to adenylate cyclase, possibly by phosphorylating the Gs protein, but other PKC isotypes must be involved in the effects observed when cells are treated with cholera toxin.
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PMID:Depletion of protein kinase C-alpha by antisense oligonucleotides alters beta-adrenergic function and reverses the phorbol ester-induced reduction of isoproterenol-induced adenosine 3'-5'-cyclic monophosphate accumulation in murine Swiss 3T3 fibroblasts. 976 65

Despite many triumphs, a significant limitation of the usefulness of many of the available B-cell lines for the study of insulin secretion are either inappropriate or lack of responsiveness to glucose. Commonly employed cell lines generated prior to the 1990s following X-ray irradiation (RINm5F cells) or simian virus 40 B-cell transformation (HIT-T15 cells and BTC) fall into this category. More recent success has been achieved with the generation of INS-1 cells and MIN6 cells, but the production of these cell lines owes much to good fortune, dedication and hard work. In the present era, molecular biology techniques provide the opportunity to engineer novel pancreatic B-cell lines which possess many attributes of normal insulin-secreting cells. This review describes the electrofusion of normal NEDH rat pancreatic B-cells with immortal RINm5F cells to create three new glucose-responsive clonal insulin-secreting cells, designated BRIN-BG5, BRIN-BG7 and BRIN-BD11. These cell lines exhibit up to four-fold insulin-secretory responses to depolarization with 25 mmol/l K+, 7.68 mmol/l Ca2+, 10 mmol/l L-alanine, and activation of protein kinase C or adenylate cyclase with 10 nmol/l phorbol- 12-myristate-13-acetate or 25 micromol/l forskolin, respectively. The maximal insulin-secretory response of both BRIN-BG5 and BRIN-BG7 cells to glucose occurred at 8.4 mmol/l (1.9- and 1.8-fold increases, respectively). In contrast, 4.2-16.7 mmol/l glucose evoked a stepwise 2- to 3-fold of insulin release from BRIN-BD11 cells. The superior glucose responsiveness of BRIN-BD11 cells compared with BRIN-BG5 or BRIN-BG7 cells was associated with increased expression of GLUT-2 and a greater contribution of glucokinase to total glucose phosphorylating enzyme activity. Furthermore, BRIN-BD11 cells also showed appropriate responses to a diverse range of modulators of pancreatic B-cell function, including amino acids, neurotransmitters and sulphonylurea drugs. Collectively these observations indicate that genetic modification of insulin-secreting cells by electrofusion (or transfection with cDNA) offers a new avenue for generation of useful clonal glucose-responsive pancreatic B-cell lines for studies of insulin secretion and transplantation in insulin-dependent diabetes mellitus.
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PMID:Engineering cultured insulin-secreting pancreatic B-cell lines. 993 Sep 71

The glycerophosphoinositols, phosphoinositide metabolites formed by Ras-dependent activation of phospholipase A2 and a lysophospholipase, have been proposed to be markers of Ras-induced cell transformation. These compounds can have important cellular effects; GroPIns4P is an inhibitor of G protein-stimulated adenylate cyclase and is transiently produced in several cell types after growth factor receptor stimulation of phosphatidylinositol 3-kinase and the small G protein Rac, indicating the importance of defining further its cellular actions and metabolism. We show here that, in postnuclear membranes from Swiss 3T3 cells, there is no high-affinity 'receptor' binding of GroPIns4P. Instead, possibly through the interaction with a transporter, GroPIns4P rapidly equilibrates between medium and cell cytosol, and, at higher concentrations, can concentrate in the cell cytosol. GroPIns4P can be dephosphorylated to GroPIns in vitro by an enzyme that is membrane-associated, Ca2+-dependent, GroPIns4P-selective and has a specific pH profile. Under in vitro phosphorylating conditions, there is production of GroPIns(4,5)P2 and other inositol phosphates. As these in vitro enzyme activities do not fully correlate with the in vivo handling of GroPIns4P, the intracellular GroPIns4P levels may be controlled by its direct physical removal from the cells.
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PMID:Membrane transport and in vitro metabolism of the Ras cascade messenger, glycerophosphoinositol 4-phosphate. 1056 81


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