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:2.7.11.11 (AMPK)
12,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In Swiss 3T3 murine fibroblasts, interleukin 1 (IL-1) and bradykinin stimulate prostaglandin E2 (PGE2) synthesis. However, in the present study, we found that neither agonist stimulated PGE2 synthesis in BALB/c 3T3 murine fibroblasts, this in spite of expression of similar numbers of receptors for each agonist compared to Swiss 3T3 cells. When BALB/c 3T3 cells were preincubated with cAMP analogs, both IL-1 and bradykinin stimulated PGE2 synthesis to levels similar to those observed in Swiss 3T3 cells. Similarly, when the cells were preincubated with forskolin, which activates the catalytic subunit of adenylate cyclase directly, or NECA, which stimulates cellular cAMP accumulation by activating adenosine receptors, IL-1 and bradykinin stimulated PGE2 synthesis. Rp-cAMPS, an inhibitor of cAMP-dependent protein kinase, blocked the ability of cAMP or NECA to render cells responsive to IL-1 and bradykinin. In basal BALB/c 3T3 cells, bradykinin and IL-1 stimulated arachidonate release in the absence of cAMP, but little conversion of released arachidonate to PGE2 occurred. cAMP, forskolin, and NECA all increased cyclooxygenase activity in the cells. SV-T2 is a clonal line originating from BALB/c 3T3 transformed with SV-40. In these cells, IL-1 and bradykinin stimulated PGE2 synthesis despite basal intracellular cAMP concentrations similar to BALB/c, and cAMP only modestly potentiated the response. In summary, cyclooxygenase expression appears to be regulated by cAMP in BALB/c 3T3 cells, and SV-40 transformation results in increased cyclooxygenase expression, apparently independent of cAMP.
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PMID:Elevated cAMP is required for stimulation of eicosanoid synthesis by interleukin 1 and bradykinin in BALB/c 3T3 fibroblasts. 133 33

Lutropin (LH) receptors in rat granulosa cells are expressed by activation of cAMP-dependent protein kinase in response to follitropin (FSH). In the present study, 12-O-tetradecanoylphorbol 13-acetate (TPA) could cause a dose-dependent expression of LH receptors in the presence of insulin, but not in the absence of insulin, as measured by binding of 125I-deglycosylated human choriogonadotropin (DGhCG). The synergistic action of TPA with insulin was achieved at 1 nM and 10 mIU/ml, respectively. The receptor expression induced by this synergistic action was accompanied by cAMP accumulation which was detected after a lag time of 6 h following exposure to TPA. However, a synthetic diacylglycerol and non-protein kinase C activating phorbol derivatives did not mimic the effect of TPA on the receptor expression. In addition, insulin modulated the inhibitory effect of TPA in FSH-induced LH receptor expression, indicating a peculiar action of insulin in the receptor expression. Indomethacin treatment led to a dose-dependent inhibition in the receptor expression in the cells treated with TPA plus insulin more than that in the cells with FSH plus insulin, suggesting that the synergistic action was dependent upon cyclooxygenase and/or phospholipase A2 activity. It was shown by Scatchard analysis of LH receptors and kinetic studies of hCG-stimulated cAMP formation that the synergistic action of TPA with insulin led to expression of functional LH receptors coupled with the adenylate cyclase system in cultured granulosa cells.
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PMID:Tumor-promoting phorbol ester acts synergistically with insulin to induce lutropin receptor expression in rat granulosa cells. 166 32

Apical membrane Cl- channels control the rate of transepithelial Cl- secretion in airway epithelia. cAMP-dependent protein kinase and protein kinase C regulate Cl- channels by phosphorylation; in cystic fibrosis cells, phosphorylation-dependent activation of Cl- channels is defective. Another important signaling system involves arachidonic acid, which is released from cell membranes during receptor-mediated stimulation. Here we report that arachidonic acid reversibly inhibited apical membrane Cl- channels in cell-free patches of membrane. Arachidonic acid itself inhibited the channel and not a cyclooxygenase or lipoxygenase metabolite because (i) inhibitors of these enzymes did not block the response, (ii) fatty acids that are not substrates for the enzymes had the same effect as arachidonic acid, and (iii) metabolites of arachidonic acid did not inhibit the channel. Inhibition occurred only when fatty acids were added to the cytosolic surface of the membrane patch. Unsaturated fatty acids were more potent than saturated fatty acids. Arachidonic acid inhibited Cl- channels from both normal and cystic fibrosis cells. These results suggest that fatty acids directly inhibit apical membrane Cl- channels in airway epithelial cells.
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PMID:Fatty acids inhibit apical membrane chloride channels in airway epithelia. 169 96

The sequence of events within the ovary during the process of ovulation discussed in this review is schematically represented in Fig. 1. It is obvious that LH, perhaps with some contribution from FSH, is the normal physiological trigger for the ovulatory sequence of events, and it appears from the available information that the effects of LH are mainly mediated via adenylate cyclase and increased cAMP levels. The cAMP in turn, via cAMP-dependent protein kinase, influences at least three distinct steps in the ovulatory process which seem to be of crucial importance, namely 1) the stimulation of steroidogenesis; 2) the stimulation of cyclooxygenase/lipooxygenase leading to increased prostaglandin/leukotriene synthesis; and 3) the stimulation of plasminogen activator which catalyzes the conversion of plasminogen to plasmin. A fourth crucial step in the ovulatory mechanism is the LH-induced increase in latent collagenase, but it remains to be determined if this step is mediated via cAMP. Concomitant with the increase in latent collagenase, there also appears to be an LH-dependent increase in collagenase inhibitors. The latent collagenase is then activated, and it appears that leukotrienes and prostaglandins, as well as plasmin, may be involved in this process. The active collagenase causes a digestion of the collagen in the follicle wall, and plasmin, as well as possibly other proteolytic enzymes such as proteoglycanases, may cause a further dissociation of the follicular wall. These processes of digestion of collagen and dissociation of the collagen fibers result in an opening in the follicular wall with the formation of the stigma and rupture. While the weakening of the follicular wall takes place throughout the entire wall, rupture remains for the most part a localized process at the apex of the follicle. This localization of the rupture may be explained on the basis of mechanical factors operating when the follicle wall thins and weakens. While it is clear that prostaglandins and leukotrienes can influence smooth muscle by causing contractions and that these compounds can cause vascular changes such as increased permeability, vasodilation, and vasoconstriction, it is not clear what the exact role of these latter processes are in ovulation. It appears that progesterone and not estrogen play an important role in the mechanism of LH-induced follicular rupture, but the locus of action of progesterone and its mechanism of action remains to be determined.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanism of mammalian ovulation. 255 97

The sequence of ovarian events during the process of ovulation discussed in this review is schematically represented in Figure 1. It is obvious that LH, perhaps with some contribution from FSH, is the normal physiological trigger for the ovulatory sequence of events and it appears from the available information that LH's effects are mainly mediated via adenylate cyclase and increased cAMP. The cAMP in turn, via cAMP-dependent protein kinase, influences at least three distinct steps in the ovulatory process which seem to be of crucial importance, namely 1) the stimulation of steroidogenesis; 2) the stimulation of cyclooxygenase/lipooxygenase leading to increased prostaglandin/leukotriene synthesis; and 3) the stimulation of plasminogen activator which catalyzes the conversion of plasminogen to plasmin. A fourth crucial step in the ovulatory mechanism is the LH-induced increase in latent collagenase, but it remains to be determined if this step is mediated via cAMP. Concomitant with the increase in latent collagenase, there also appears to be an LH-dependent increase in collagenase inhibitors. The latent collagenase is then activated and it appears that leukotrienes and prostaglandins as well as plasmin may be involved in this process. The active collagenase causes a digestion of the collagen in the follicle wall. Plasmin as well as possibly other proteolytic enzymes such as proteoglycanases (Too et al., 1984) may cause a further dissociation of the follicular wall. These processes of digestion of collagen and dissociation of the collagen fibers result in an opening in the follicular wall with the formation of the stigma and rupture. While the weakening of the follicular wall takes place throughout the entire wall, rupture remains for the most part a localized process at the apex of the follicle. This localization of the rupture may be explained on the basis of mechanical factors operating when the follicle wall thins and weakens (Rodbard, 1984). While it is clear that prostaglandins and leukotrienes can influence smooth muscle by causing contractions and that these compounds can cause vascular changes such as increased permeability, vasodilatation and vasoconstriction, it is not clear what the exact role of these latter processes are in ovulation. It appears that progesterone and not estrogen play an important role in the mechanism of LH induced follicular rupture, but the locus of action of progesterone and its mechanism of action remains to be determined.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanism of mammalian ovulation. 265 83

Stimulation of Ca2+ mobilization and entry by agonists such as ADP, thrombin, and thromboxane is an early step of platelet activation. Here, we compared the effects of adenosine 3',5'-cyclic monophosphate (cAMP)-elevating prostaglandins, guanosine 3',5'-cyclic monophosphate (cGMP)-elevating nitrovasodilators, membrane-permeant selective activators of cAMP- or cGMP-dependent protein kinases, and physiological endothelium-derived factors on the agonist-evoked Ca2+ mobilization and entry in human platelets. Prostaglandin E1, the prostacyclin analogue Iloprost, the nitric oxide (NO) donor 3-morpholinosydnonimine hydrochloride, and selective activators of cGMP- or cAMP-dependent protein kinase strongly inhibited the agonist-evoked Ca2+ mobilization from intracellular stores and associated late Ca2+ entry but had little effects on the rapid (1st) phase of ADP-evoked Ca2+ entry. During coincubation of platelets with endothelial cells, endothelium-derived factors that were released strongly inhibited platelet agonist-evoked Ca2+ mobilization and only moderately affected the rapid phase of ADP-evoked Ca2+ entry. These effects were partially prevented when endothelial cells were preincubated with cyclooxygenase and/or NO synthase inhibitors. Endothelial cells therefore produce sufficient quantities of labile platelet inhibitors whose effects on the platelet Ca2+ response resemble those observed with selective cAMP- and cGMP-dependent protein kinase activators.
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PMID:Regulation of calcium mobilization and entry in human platelets by endothelium-derived factors. 804 83

The ACTH response to endogenous or exogenous CRH is increased in patients with myotonic dystrophy (DM), possibly because of abnormal function of cAMP-dependent protein kinases in this condition. Arachidonic acid (AA) metabolites are believed to interact with the cAMP-dependent second messenger system activated by CRH; therefore, drugs that interfere with AA metabolism may alter ACTH secretion in DM. In this study, seven DM patients were given naloxone, which stimulates endogenous CRH release, and aspirin, which inhibits the synthesis of prostaglandins from AA via the cyclooxygenase metabolic pathway. Pretreatment with aspirin reduced the mean integrated ACTH response to naloxone by 33% (P < 0.05). However, the corresponding 18% reduction in cortisol levels was not statistically significant (P > 0.10). These findings are in contrast to those of a previous study using an identical protocol, in which aspirin increased the ACTH response to naloxone in six normal volunteers. This difference between DM and control subjects is consistent with the hypothesis that the interaction between AA metabolites and the cAMP-dependent protein kinase-A second messenger system is abnormal in the corticotrophs of persons with DM.
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PMID:Paradoxical inhibition by aspirin of naloxone-induced adrenocorticotropin secretion in myotonic dystrophy. 820 Sep 45

Arachidonic acid (AA) stimulated protein phosphorylation in electrically permeabilised islets, most notably of an islet protein of approximate molecular weight 18 kDa. This protein did not appear to be a substrate for cAMP-dependent protein kinase. The AA-induced protein phosphorylation was mediated by unmetabolised AA since the lipoxygenase inhibitor, nordihydroguaretic acid (NDGA), or the cyclooxygenase inhibitor, indomethacin, did not significantly reduce AA-induced phosphorylation. Although saturated fatty acids did not stimulate phosphorylation of islet proteins, a number of cis-unsaturated fatty acids, other than AA, induced 32P incorporation into an 18 kDa protein. However, some fatty acids which stimulated protein phosphorylation had no effect on insulin secretion in experiments where AA clearly stimulated insulin secretion. AA stimulated protein kinase C (PKC) activity extracted from islets but several fatty acids which induced protein phosphorylation had no significant effect on PKC activity in vitro. 50 nM staurosporine had no effect on AA-induced protein phosphorylation but this concentration of staurosporine markedly inhibited PKC activity. 200 nM staurosporine caused complete inhibition of the AA-induced phosphorylation without having any effect on AA-induced insulin secretion. These results suggest that AA and some other fatty acids can promote 32P incorporation into islet proteins, independently of PKC activation, and that AA-induced phosphorylation is not required for insulin secretory responses to AA.
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PMID:Arachidonic acid-induced insulin secretion from rat islets of Langerhans is not mediated by protein phosphorylation. 838 12

The abilities of platelet-derived growth factor (PDGF) and insulin-like growth factor (IGF-I) to regulate cAMP metabolism and mitogen-activated protein kinase (MAP kinase) activity were compared in human arterial smooth muscle cells (hSMC). PDGF-BB stimulated cAMP accumulation up to 150-fold in a concentration-dependent manner (EC50 approximately 0.7 nM). The peak of cAMP formation and cAMP-dependent protein kinase (PKA) activity occurred approximately 5 min after the addition of PDGF and rapidly declined thereafter. Incubating cells with PDGF and 3-isobutyl-1-methylxanthine (IBMX, a phosphodiesterase inhibitor) enhanced the accumulation of cAMP and PKA activity by an additional 2.5-3-fold, whereas IBMX alone was essentially without effect. The PDGF-stimulated increase in cAMP was prevented by addition of the cyclooxygenase inhibitor indomethacin, consistent with release of prostaglandins stimulating cAMP. PDGF, but not IGF-I, stimulated MAPK activity, cytosolic phospholipase A2 (cPLA2) phosphorylation, and cAMP synthesis which indicated a key role for MAP kinase in the activation of cPLA2. Further, PDGF stimulated the rapid release of arachidonic acid and synthesis of prostaglandin E2 (PGE2) which could be inhibited by a cPLA2 inhibitor (AACOCF3). Calcium mobilization was required for PDGF-induced arachidonic acid release and PGE2 synthesis but not for MAPK activation, whereas PKC was required for PGE2-mediated activation of PKA. In summary, these results demonstrated that PDGF increases cAMP formation and PKA activity through a MAP kinase-mediated activation of cPLA2, arachidonic acid release, and PGE2 synthesis in human arterial smooth muscle cells.
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PMID:Platelet-derived growth factor stimulates protein kinase A through a mitogen-activated protein kinase-dependent pathway in human arterial smooth muscle cells. 855 Jun 11

Nimesulide (CAS 51803-78-2) has been shown to exert a marked anti-inflammatory effect in several in vivo models of inflammation. Recent studies indicate that nimesulide not only inhibits prostaglandin synthesis in certain cell types, but also has pleiotropic effects on neutrophil functions, including the respiratory burst, integrin-mediated adherence and synthesis of platelet-activating factor (PAF). In the present study, the effect of nimesulide on PAF synthesis was compared with its effect on the production of leukotriene B4 (LTB4). Nimesulide dose-dependently inhibited both processes in neutrophils stimulated by serum-treated zymosan (STZ) with a comparable efficacy (IC50 values between 10 and 20 mumol/l). In formyl-methionyl-leucyl-phenylalanine-stimulated neutrophils (treated with cytochalasin B), these IC50 values were 30 and 50 mumol/l for PAF and LTB4 synthesis, respectively. These results indicate an inhibition by nimesulide of a common step in the release of these lipid mediators, i.e. the activation of phospholipase A2, possibly by elevating intracellular cAMP. In support of this latter hypothesis, it was observed that nimesulide increased the level of cAMP almost 3-fold after STZ stimulation, whereas in fMLP-stimulated neutrophils these changes in cAMP levels were more dramatic. Furthermore, the inhibitory effects of nimesulide on PAF and LTB4 production could largely be prevented by addition of H89, an inhibitor of cAMP-dependent protein kinase (PK-A). It is concluded that an increase in intracellular cAMP is instrumental in the observed effects of nimesulide on the release of PAF and LTB4 by activated neutrophils and that limited availability of arachidonic acid, also the substrate for the cyclooxygenase pathway, may very well contribute to the effects of nimesulide on prostaglandin synthesis observed in other cell types.
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PMID:Inhibition of the production of platelet activating factor and of leukotriene B4 in activated neutrophils by nimesulide due to an elevation of intracellular cyclic adenosine monophosphate. 859 70


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