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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adrenaline has recently been shown to stimulate both glucose metabolism and H2O2 release by macrophages but the activity of the key pentose phosphate pathway enzyme, glucose-6-phosphate dehydrogenase (which generates the NADPH crucial for the reduction of molecular oxygen), was reduced under these conditions [Costa Rosa, Safi, Cury and Curi (1992) Biochem. Pharmacol. 44, 2235-2241]. We report here that adrenaline activates another NADPH-producing enzyme, NADP(+)-dependent 'malic' enzyme, while also inhibiting glucose-6-phosphate dehydrogenase, via cyclic AMP-dependent protein kinase (PKA) activation. Regulation of glucose-6-phosphate dehydrogenase activity by PKA has not been reported elsewhere. The sparing of some glucose from pentose phosphate pathway consumption may be important in the provision of glycerol 3-phosphate which in the macrophage may be required for new phospholipid synthesis. Glutamine oxidation was also stimulated by adrenaline thus providing increased substrate (malate) for NADP(+)-dependent 'malic' enzyme and therefore shifting some of the burden of NADPH production from glucose to glutamine metabolism. We also report a novel synergistic effect of adrenaline and some bacterial products and/or gamma-interferon in stimulating secretory and metabolic pathways in macrophages which may be a part of a larger network of signals that lead to enhanced macrophage activity.
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PMID:Effect of adrenaline and phorbol myristate acetate or bacterial lipopolysaccharide on stimulation of pathways of macrophage glucose, glutamine and O2 metabolism. Evidence for cyclic AMP-dependent protein kinase mediated inhibition of glucose-6-phosphate dehydrogenase and activation of NADP+-dependent 'malic' enzyme. 765 15

The involvement of adenosine 3',5'-cyclic monophosphate (cAMP) in the stimulation of ventricular protein synthesis by aortic hypertension or adrenergic agonists in the adult rat heart was investigated. In either the retrogradely or anterogradely perfused heart, aortic hypertension increased protein synthesis rates by up to 19%. However, no changes in cAMP concentrations or in cAMP-dependent protein kinase activity ratios could be detected either at early (< 5 min) or late (90 min) time points. Although isoproterenol, 3-isobutyl-1-methylxanthine, or forskolin raised cAMP concentrations (by up to 4.5-fold) and cAMP-dependent protein kinase ratios (by up to 4-fold), protein synthesis rates were not increased; however, under some perfusion conditions, glucagon did stimulate protein synthesis by 25%. Epinephrine stimulated protein synthesis by up to 32%, an effect that was not prevented by propranolol. Phenylephrine also stimulated protein synthesis, an effect that was prevented by prazosin but was unaffected by yohimbine. These findings implicate the alpha 1-adrenoceptor in the regulation of cardiac protein synthesis. Because changes in adenine nucleotide concentrations were similar in hearts perfused with epinephrine or with the agents that raised cAMP, it is unlikely that adenine nucleotide depletion is responsible for the failure to observe effects of the latter group of agents on protein synthesis. Although isoproterenol or forskolin raised cAMP concentrations in isolated ventricular cardiomyocytes where ATP depletion was minimal, neither stimulated protein synthesis. alpha 1-Adrenergic agonists stimulate phosphoinositide hydrolysis in the heart (Brown, J. H., I. L. Buxton, and L. L. Brunton. Circ. Res. 57:532-537, 1985). Aortic hypertension doubled the rate of phosphoinositide hydrolysis in the perfused heart. We suggest that the phosphoinositide-linked signal transduction pathway is more likely to be involved in stimulation of cardiac protein synthesis by hypertension or adrenergic agonism than the adenylyl cyclase/cAMP-linked pathway.
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PMID:cAMP and protein synthesis in isolated adult rat heart preparations. 769 91

Dehydroepiandrosterone sulfate is the major steroid secretory product of the human fetal adrenal gland. Several factors have been shown to modulate the secretion of this steroid by cultured fetal adrenal cells. In addition to the cytochrome P450 enzymes that are important in steroid biosynthesis, dehydroepiandrosterone sulfotransferase (DST) is likely to be a key regulated enzyme in the formation of sulfated steroids, which are characteristic of the human adrenal cortex, particularly that of the fetus and the adult zona reticularis. In the present investigation, we sought to evaluate the cellular localization of DST in cultures derived from the fetal zone, neocortex, and adrenal capsule and to determine the effects of ACTH and other agonists of the protein kinase-A pathway on the abundance of DST in such cells. Cells derived from the fetal zone, neocortex, and adrenal capsule were either precultured for 3-13 days in plastic flasks followed by culture on coverslips or were cultured directly on coverslips in control medium (McCoy's 5A medium that contained 5% fetal bovine serum) or control medium plus ACTH, forskolin, or dibutyryl cAMP for 1-4 days. Cells were fixed in buffered formalin and then immunostained for DST by use of a rabbit polyclonal antiserum prepared against human liver DST. DST immunoreactivity was abundant in freshly isolated cortical cells derived from fetal zone and neocortex. DST immunoreactivity was still observable in fetal zone and neocortex cells as well as in cells prepared from enzymatic digests of adrenal capsule after scraping off adherent neocortex cells following culture for 9-14 days in control medium. Adrenal fibroblasts were negative for DST. DST abundance in cortical cells was increased in cultures supplemented with ACTH, forskolin, or dibutyryl cAMP compared to that in cultures grown in control medium alone. The results of Western blot analyses of DST in these cells were consistent with the immunocytochemical data. These results suggest that DST is present in both fetal zone and neocortex cells of the human fetal adrenal at midgestation and that the production of DST is stimulated by ACTH and agonists of the protein kinase-A signal transduction pathway in the human fetal adrenal gland.
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PMID:Immunocytochemical analyses of dehydroepiandrosterone sulfotransferase in cultured human fetal adrenal cells. 788 17

Dehydroepiandrosterone sulfate is the major steroid secretory product of the human fetal adrenal gland. Several factors have been shown to modulate the secretion of this steroid by cultured fetal adrenal cells. In addition to the cytochrome P450 enzymes that are important in steroid biosynthesis, dehydroepiandrosterone sulfotransferase (DST) is likely to be a key regulated enzyme in the formation of sulfated steroids, which are characteristic of the human adrenal cortex, particularly that of the fetus and the adult zona reticularis. In the present investigation, we sought to evaluate the cellular localization of DST in cultures derived from the fetal zone, neocortex, and adrenal capsule and to determine the effects of ACTH and other agonists of the protein kinase-A pathway on the abundance of DST in such cells. Cells derived from the fetal zone, neocortex, and adrenal capsule were either precultured for 3-13 days in plastic flasks followed by culture on coverslips or were cultured directly on coverslips in control medium (McCoy's 5A medium that contained 5% fetal bovine serum) or control medium plus ACTH, forskolin, or dibutyryl cAMP for 1-4 days. Cells were fixed in buffered formalin and then immunostained for DST by use of a rabbit polyclonal antiserum prepared against human liver DST. DST immunoreactivity was abundant in freshly isolated cortical cells derived from fetal zone and neocortex. DST immunoreactivity was still observable in fetal zone and neocortex cells as well as in cells prepared from enzymatic digests of adrenal capsule after scraping off adherent neocortex cells following culture for 9-14 days in control medium. Adrenal fibroblasts were negative for DST. DST abundance in cortical cells was increased in cultures supplemented with ACTH, forskolin, or dibutyryl cAMP compared to that in cultures grown in control medium alone. The results of Western blot analyses of DST in these cells were consistent with the immunocytochemical data. These results suggest that DST is present in both fetal zone and neocortex cells of the human fetal adrenal at midgestation and that the production of DST is stimulated by ACTH and agonists of the protein kinase-A signal transduction pathway in the human fetal adrenal gland.
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PMID:Immunocytochemical analyses of dehydroepiandrosterone sulfotransferase in cultured human fetal adrenal cells. 777 16

Fast-flow perfusion and flash photolysis of caged compounds were used to study the activation kinetics of L-type calcium current (ICa) in frog cardiac myocytes. Rapid exposure to isoproterenol (Iso) for 1 s or approximately 1 min produced similar kinetics of increase in ICa with an initial lag period of approximately 3 s, followed by a monophasic rise in current with a half-time of approximately 20 s. Epinephrine, as well as caged Iso, produced increases with similar kinetics. The fact that ICa increased significantly even after short Iso applications suggests that agonist binding to the receptor is rapid and that the increase in ICa is independent of free agonist. To dissect the kinetic contributions of various steps in the cAMP-phosphorylation cascade, the kinetics of the responses to caged cAMP and caged GTP gamma S and fast perfusion of forskolin, acetylcholine, and propranolol were compared. The response to caged cAMP exhibited no lag period, but otherwise increased at a rate similar to that produced by Iso and reached a peak at approximately 40 s after flash photolysis. This suggests that the lag period itself is due to a step before cAMP accumulation, but that activation of protein kinase and phosphorylation of the calcium channel are relatively slow. A lag period was also observed when ICa was stimulated by flash photolysis of caged GTP gamma S and when adenylyl cyclase was activated directly by rapid perfusion with forskolin. The lag period observed with forskolin may be due to slow binding of forskolin. The lag period was not due to the time required for cAMP to reach a threshold concentration, because a similar lag was observed in response to Iso in cells having ICa previously stimulated submaximally by internal perfusion with a low concentration of cAMP. These results suggest that the lag period can be attributed to a step associated with activation of adenylyl cyclase and cAMP accumulation.
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PMID:Rate-limiting steps in the beta-adrenergic stimulation of cardiac calcium current. 838 16

In the present study wild-type and various mutant hamster beta 2-adrenergic receptors (beta ARs) expressed in L cells were used to examine potential molecular mechanisms involved in the desensitization of hormonal stimulation of adenylyl cyclase observed after long term exposure to low concentrations of epinephrine. The mutant beta ARs included deletion mutants, D(259-262)beta AR and D(343-348)beta AR, that lack the consensus sites for cAMP-dependent protein kinase (cAPK) and protein kinase C (PKC) and a truncation mutant, T(354)beta AR, that lacks the putative consensus sites for beta AR kinase. Epinephrine stimulation of adenylyl cyclase was desensitized in all four cell lines after growth for 24 hr in the presence of 3 nM epinephrine, and this desensitization was characterized by a 3-4-fold increase in the EC50 for epinephrine stimulation of adenylyl cyclase. In addition, the Vmax was significantly decreased in the cells with the wild-type beta AR and the D(343-348)beta AR. The desensitization was not masked by high concentrations of magnesium and was accompanied by a 40-70% down-regulation of beta ARs. In the cells treated with 3 nM epinephrine, prostaglandin E1 stimulation of adenylyl cyclase was decreased 11% in cells with the wild-type beta AR and forskolin stimulation was decreased 25-36% with all but the D(259-262)beta AR mutant. These results demonstrated that phosphorylations of the cAPK/PKC consensus sites and the serine- and threonine-rich segment of the carboxyl-terminal tail of the beta AR were not required for the desensitization caused by 3 nM epinephrine, thus further differentiating it from cAPK- or PKC-mediated desensitization and the desensitization attributed to beta AR kinase.
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PMID:Beta 2-adrenergic receptor mutants reveal structural requirements for the desensitization observed with long-term epinephrine treatment. 839 17

Adrenal corticosteroids have well known and profound effects on neurons and neuroendocrine cells, but the underlying cellular mechanisms are poorly understood. The present study analyzed membrane currents and ACTH release in AtT20 mouse pituitary corticotrope tumor cells. Patch-clamp analysis revealed a significant and selective inhibition of calcium-activated (BK-type) potassium channels upon activation of protein kinase A by corticotropin-releasing factor or 8-chlorophenylthio-cAMP. The synthetic glucocorticoid dexamethasone had no effect on potassium currents evoked by depolarization but prevented the inhibitory effect of protein kinase A activators. The action of dexamethasone had the hallmarks of protein induction, i.e. a lag time and sensitivity to inhibitors of DNA transcription and mRNA translation. In parallel, the specific BK channel blocker iberiotoxin abolished early glucocorticoid inhibition of corticotropin-releasing factor-stimulated ACTH secretion. In summary, the present data show that glucocorticoid-induced proteins render BK-type channels resistant to inhibition by protein kinase A and that this action of the steroid is pivotal for its early inhibitory effect on the secretion of ACTH.
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PMID:Glucocorticoids block protein kinase A inhibition of calcium-activated potassium channels. 862 76

Phenobarbital (PB) induces CYP1A1 at the transcriptional level and causes nuclear translocation of the aromatic hydrocarbon (Ah) receptor in primary cultures of rainbow trout hepatocytes (1). The results from this study suggest that PB induction of CYP1A1 in rainbow trout hepatocytes is regulated by cAMP-dependent pathways (PKA), whereas TCDD induction is not dependent upon PKA. Epinephrine, which increases cAMP levels and activates PKA-dependent pathways, was a potent inhibitor of PB induction, while having no effect on TCDD induction of CYP1A1 gene expression. When PKA-dependent pathways were inhibited, PB induction of CYP1A1 gene expression was greatly potentiated, whereas TCDD induction was affected to a lesser extent. Inhibitors of calcium-phospholipid-dependent protein kinase (PKC) had modest or no effect on PB and TCDD induction of CYP1A1, respectively. Whether the relatively weak-to-no inhibition of CYP1A1 in response to PKC inhibitors in fish is due to differences in the types and levels of PKC isoenzymes, cell permeability, protocol, or the role of PKC in the mechanism of CYP1A1 induction in fish remains to be established. PB induced persistent and transient increases in the intracellular calcium concentration. This may be an important factor regulating PKC which may have a role in PB-mediated induction of CYP1A1 gene transcription.
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PMID:Phenobarbital induction of cytochrome P4501A1 is regulated by cAMP-dependent protein kinase-mediated signaling pathways in rainbow trout hepatocytes. 875 83

Adrenal steroid hormone biosynthesis can be activated by the protein kinase A pathway by ACTH, the protein kinase C pathway by angiotensin II (AII), or by increasing intracellular Ca2+ levels by AII or K+. Although their mechanisms of action are not known, each of these pathways is dependent upon the de novo synthesis of a protein that is required for the acute production of steroids. We have recently proposed the steroidogenic acute regulatory (StAR) protein as this required protein, therefore, we examined the effect of different agonists on StAR's expression in H295R human adrenocortical carcinoma cells. (Bu)2cAMP, AII, K+, BAYK8644 (a calcium channel agonist) and TPA are all shown to induce StAR. Aldosterone synthesis was stimulated by all the agonists with the exception of TPA, indicating that AII-stimulated steroid production is mediated by increases in intracellular calcium. Thus, these data suggest that regulation of StAR expression may represent a common mechanism for divergent pathways to acutely control adrenal steroidogenesis.
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PMID:The steroidogenic acute regulatory protein is induced by angiotensin II and K+ in H295R adrenocortical cells. 882 97

We have demonstrated previously that protein kinase Calpha (PKCalpha) plays a key role in regulating phospholipase D (PLD) activation by nucleotides and the phorbol ester phorbol-12-myristate-13-acetate in Madin-Darby canine kidney (MDCK-D1) cells. In the current work, we investigated PLD activation in MDCK-D1 cells triggered by the adrenergic receptor agonist epinephrine and its mechanism of activation. Epinephrine, acting through the alpha1-adrenergic receptor subtype, promoted transient translocation of PKCalpha and more prolonged translocation of PKCepsilon to the membrane fraction, indicating activation of these two isoforms. In addition, epinephrine promoted activation of PLD, as shown by a sustained accumulation of phosphatidylethanol. All of these events were blocked by pretreatment of cells with the alpha1-adrenergic antagonist prazosin. D609, an inhibitor of phosphatidylcholine hydrolysis, blocked translocation of PKCalpha and PKCepsilon but did not inhibit PLD activation. Unlike results with PMA, or with the P2 purinergic receptor agonist ATP, epinephrine-stimulated PLD activity was not inhibited in MDCK-D1 cells in which PKCalpha expression is attenuated by an antisense cDNA construct or in cells in which PKC activity was inhibited by 1 microM GF 109203X. However, PLD activation by epinephrine was abolished by concomitant incubation of cells with the calcium chelator EGTA. These data, together with previous results, are consistent with the hypothesis that in MDCK-D1 cells, epinephrine acting on alpha1-adrenergic receptors, promotes a rapid increase in cytosolic Ca2+ that promotes activation of PLD through an as-yet poorly defined mechanism. The data demonstrate that different types of G protein-linked receptors that activate PLD can mediate this activation in either a PKC activation-dependent or -independent manner within a single cell type.
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PMID:Stimulation of phospholipase D via alpha1-adrenergic receptors in Madin-Darby canine kidney cells is independent of PKCalpha and -epsilon activation. 946 79


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