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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The objective of this study was to investigate the effects of 4 beta-phorbol 12-myristate 13-acetate (4 beta-PMA)--a potent activator of protein kinase C--on the responsiveness of mouse Leydig cells to stimulation with rat atriopeptin II (rAP-II). We report that, in these cells, the stimulation of testosterone production by rAP-II could be inhibited in a dose-dependent manner by 4 beta-PMA (1-200 nM). In contrast, the basal steroidogenesis was stimulated 2-fold by 4 beta-PMA. There was no inhibition of testosterone production when the cells were stimulated with 8-bromo cyclic GMP (8Br-cGMP) in the presence of 4 beta-PMA. Furthermore, addition of 4 beta-PMA resulted in a marked reduction in the amount of cGMP accumulated in response to rAP-II stimulation. 4 alpha-Phorbol 12-myristate 13-acetate (4 alpha-PMA) was found to have no effect at all. The inhibitory effect of 4 beta-PMA on steroidogenesis could be completely reversed by the addition of 0.25 mM 3-isobutyl 1-methylxanthine (IBMX), a phosphodiesterase inhibitor. Also, the 4 beta-PMA-induced lowering of cGMP content could be partially reversed by IBMX. Membrane fractions from cells treated with 4 beta-PMA or 4 alpha-PMA did not differ in their contents of either basal or rAP-II-stimulated guanylate cyclase activities. We conclude that the 4 beta-PMA-mediated inhibition of testosterone production by Leydig cells stimulated with rAP-II results from an activation of a phosphodiesterase enzyme, hypothetically through an activated protein kinase C. This leads to a reduction in the cellular cGMP content through an increased metabolic removal of cGMP formed in response to rAP-II stimulation.
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PMID:Effect of a tumour-promoting phorbol ester on atrial peptide-induced testosterone production and cyclic GMP accumulation by isolated mouse Leydig cells. 283 43

Protein kinase C activators (e.g. PMA) inhibit the inositol phosphate release generated by crosslinking antigen receptors (sIgM and sIgD) on murine B lymphocytes with anti-receptor antibodies. Unlike other Ca2+-mobilizing receptor systems, the antigen receptor signal transduction pathway in B cells is not interrupted by PMA at the level of receptor/G-protein or G-protein/polyphosphoinositide phosphodiesterase coupling. In these cells, PMA, presumably by activating protein kinase C, inhibits inositol phosphate release by direct effects on the polyphosphoinositide-specific phosphodiesterase.
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PMID:Protein kinase C activators inhibit the antigen receptor-coupled polyphosphoinositide phosphodiesterase in murine B lymphocytes. 284 59

The term 'stimulus-secretion coupling' has, since first enunciated, been held to involve the mobilization of cytosol Ca2+, which in turn is sufficient to trigger exocytotic secretory processes in metabolically competent cells. However, recent studies on a wide range of secretory cell types indicate that a role for Ca2+ can be obviated: examples are stimulation with phorbol ester (phorbol myristate acetate, PMA) which causes the activation of protein kinase C or the stimulation of platelets with collagen. Ca2+-independent exocytosis also occurs when analogues of GTP are injected through the lumen of patch pipettes directly into the cytosol of mass cells. The results presented here suggest that GTP analogues can activate secretory processes by actions at two distinct locations: one may be at the level of the receptor involving the activation of polyphosphoinositide (PPI) phosphodiesterase with consequent liberation of diacylglycerol (DG); the other involves direct activation of the exocytotic mechanism. These conclusions are based on measurements of exocytotic secretion from permeabilized neutrophils into which we have been able to introduce, individually and in combination, Ca2+ chelators (EGTA and BAPTA), Ca2+ (buffered at micromolar concentrations with EGTA), analogues of GTP and GDP and the direct activator of protein kinase C, PMA.
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PMID:Two roles for guanine nucleotides in the stimulus-secretion sequence of neutrophils. 300 81

Hepatocytes were isolated from rats and then loaded with the fluorescent Ca2+ indicator quin2. Glucagon caused a sustained increase (at least 5 min) in the fluorescence of the quin2-loaded cells; the increase was much greater than that observed with control, non-quin2-loaded, cells. These observations indicate that glucagon caused an increase in cytoplasmic free Ca2+ concentration [( Ca2+]c). The effects of glucagon were mimicked if forskolin (to activate adenylate cyclase), dibutyryl cyclic AMP or bromo cyclic AMP were added directly to the cells. Thus an increase in cyclic AMP concentration may mediate the effect of glucagon on [Ca2+]c. If 4 beta-phorbol 12-myristate 13-acetate (PMA; an activator of protein kinase C) was added to the cells before glucagon, the magnitude of the increase in [Ca2+]c was greatly diminished. If PMA was added after glucagon it caused a lowering of [Ca2+]c. These effects of PMA on the glucagon-induced increase in [Ca2+]c could not be mimicked if [Ca2+]c was increased by the Ca2+-ionophore ionomycin. Thus an event involved in the mechanism by which glucagon increases [Ca2+]c appears to be required for the action of PMA. If [Ca2+]c was increased by forskolin, dibutyryl cyclic AMP or bromo cyclic AMP, the effect of PMA on [Ca2+]c was similar to that observed when glucagon was used to elevate [Ca2+]c. When [Ca2+]c was raised by dibutyryl cyclic AMP the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine did not prevent the subsequent addition of PMA from causing [Ca2+]c to decrease. These observations suggest that PMA can inhibit the cyclic AMP-induced increase in [Ca2+]c independently of any changes in cyclic AMP concentration. Glucagon appears to increase [Ca2+]c by releasing intracellular stores of Ca2+ and stimulating net influx of Ca2+ into the cell; PMA greatly diminishes both of these effects.
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PMID:4 beta-Phorbol 12-myristate 13-acetate attenuates the glucagon-induced increase in cytoplasmic free Ca2+ concentration in isolated rat hepatocytes. 302 59

The tumour-promoting phorbol ester, PMA (phorbol 12-myristate 13-acetate), markedly reduced the steroidogenic response of mouse Leydig cells to stimulation by hCG and cholera toxin. However, 8Br-cAMP-and forskolin-stimulated steroidogenesis was not inhibited by PMA. PMA did not inhibit hCG-induced steroidogenesis in the simultaneous presence of 1 microM forskolin. The analysis of intracellular cAM P indicated that the PMA-induced inhibition of steroidogenesis was the result of an impaired cAMP accumulation. Adenylate cyclase in membranes prepared from PMA-treated cells showed a diminished response to hCG, GTP, guanosine 5'-[beta, gamma-imido]triphosphate [Gpp(NH)p] or to a combination of the stimulants. PMA, however, was unable to inhibit adenylate cyclase when added directly to the membrane preparation from untreated cells. As previous observations have indicated that 125I-hCG binding and phosphodiesterase activity in mouse Leydig cells are not influenced by PMA, it is concluded from the present study that the site of inhibition has to be localised to the regulatory guanine nucleotide binding protein of the adenylate cyclase system.
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PMID:Inhibition of hCG-stimulated adenylate cyclase in purified mouse Leydig cells by the phorbol ester PMA. 404 Apr 75

Preincubation of AtT-20 mouse pituitary tumour cells with the phorbol ester PMA resulted in a concentration-dependent inhibition of CNP-stimulated cyclic GMP production. The phorbol ester analogue 4 alpha phorbol had no inhibitory effect and 24 h preincubations with PMA resulted in a characteristic down-regulation of the response indicating that the inhibitory actions were mediated via the activation of protein kinase C. Forskolin in the presence of the phosphodiesterase inhibitor IBMX stimulated intracellular cyclic AMP concentrations by up to eight fold, but did not alter basal nor CNP-stimulated cyclic GMP production. These results indicate that CNP-stimulated guanylate cyclase activity associated with the GC-B natriuretic peptide receptor expressed in AtT-20 cells is inhibited by protein kinase C.
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PMID:Phorbol ester activation of protein kinase C inhibits CNP-stimulated cyclic GMP production in the mouse AtT-20 pituitary tumour cell line. 752 63

Recent evidence suggests that protein kinase A (PKA)-activated Cl- channels in heart are encoded by an isoform of the epithelial cystic fibrosis transmembrane conductance regulator gene (CFTR). Macroscopic current measurements indicate that a similar time-independent Cl- conductance can be activated through a protein kinase C (PKC)-dependent pathway in guinea pig and feline ventricle. However, it is presently not clear whether PKC is activating the same population of channels as PKA or a separate class of Cl- channels. even though the regulatory (R) domain of CFTR is known to contain consensus phosphorylation sites for both PKA and PKC. In the present study we directly compare the properties of single Cl- channels activated by PKC and PKA in cell-attached patches of guinea pig ventricular myocytes. Pipette and bath solutions contained N-methyl-D-glucamine and Cs+ or tetraethylammonium as substitutes for Na+ and K+, respectively, and Cl- concentration in the patch pipette was either 150 mmol/L or 40 mmol/L. Bath application of phorbol 12,13-dibutyrate or phorbol 12-myristate 13-acetate (PDBu or PMA; 50 nmol/L), activators of PKC, resulted in the appearance of unitary Cl- channels with a mean conductance of 9.31 +/- 0.94 pS (n = 8) and 8.8 pS (n = 2), respectively, and reversal potentials were close to predicted ECl. Addition of staurosporine (500 nmol/L) reduced open probability (Po) of channels activated by PDBu. Bath application of the phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (IBMX, 500 mumol/L) resulted in the activation of Cl- channels with a conductance (mean 8.76 +/- 0.67 pS, n = 3) similar to those activated by PDBu.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Unitary chloride channels activated by protein kinase C in guinea pig ventricular myocytes. 753 Jun 7

In this study we investigated the effect of adenosine receptor agonists on the adherence of PMA-stimulated human neutrophils to cultured porcine aortic endothelial cells. Additionally, we studied the influence of adenosine analogues on the second messenger cAMP in neutrophils and cultured endothelial cells. In the presence of 10 ng/ml PMA, there was a rapid and stable increase on adherence of neutrophils to the endothelial layer. The adenosine A2 receptor agonists, 2-(p-(2-carboxylethyl)phenethylamino)-5' N-ethylcarboxamido-adenosine (CGS 21680) (0.01 to 1 microM) and 5' N-ethylcarboxamidoadenosine (NECA) (0.01 to 1 microM) decreased the adherence of PMA-stimulated neutrophils maximally by 43% and 34%, respectively. In contrast the adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (0.01 to 1 microM) showed a 30% increase in PMA-stimulated adherence of neutrophils to endothelial cells. CGS 21680 (0.01 to 1 microM) and NECA (0.01 to 1 microM) were without detectable effect on the formation of cAMP in neutrophils and endothelial cells; however, in the presence of the phosphodiesterase inhibitor Ro 20-1724 (70 microM), CGS 21680 and NECA maximally increased cAMP level 20-fold and 10-fold, respectively, in neutrophils, and 1.8-fold and 2-fold, respectively, in cultured endothelial cells. However, addition of 70 microM Ro 20-1724 to the adherence assay did not potentiate the inhibitory effects of CGS 21680 and NECA on PMA-stimulated neutrophil adherence. On the other hand, 2-chloro-N6-cyclopentyladenosine (0.01 to 1 microM) did not significantly alter cAMP level in neutrophils and endothelial cells in the presence of 4(3-butoxy-4-methoxyphenyl)methyl)-2-imidazolidinone (Ro 20-1724). Our results indicate that adenosine A2 receptor agonists decrease phorbol ester-stimulated adherence of neutrophils to cultured endothelial cells. This effect is possibly independent of adenosine A2 receptor-mediated stimulation of adenylate cyclase in neutrophils and cultured endothelial cells.
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PMID:Phorbol ester-stimulated adherence of neutrophils to endothelial cells is reduced by adenosine A2 receptor agonists. 760 9

The neurotransmitter, pituitary adenylate cyclase-activating polypeptide (PACAP), is present in the rat adrenal medulla and is a potent stimulus for catecholamine secretion. Previous studies have suggested that neurally derived signals stimulate proliferation of chromaffin cells in adult rats. To determine whether PACAP might be involved in mitogenic signalling, its effects on bromodeoxyuridine incorporation were studied in adrenal medullary cell cultures from adult female rats. Both PACAP 27 and PACAP 38 are able to stimulate proliferation of adult rat chromaffin cells in vitro, either alone or in conjunction with PMA, an activator of protein kinase C. BrdU-labelled nuclei are observed in both epinephrine and norepinephrine cells, and proliferation of both cell types is stimulated by the same concentrations of PACAP that elicit secretion of catecholamines. The mitogenic effects of PACAP are potentiated by indolidan, a phosphodiesterase inhibitor known to cause pheochromocytomas in rats, and are inhibited by H-89, an inhibitor of protein kinase A. Mitogenic concentrations of PACAP inhibit mitogenic effects of nerve growth factor. These findings support the hypothesis that neurally derived signals regulate chromaffin cell proliferation in adult rats. Indolidan and a variety of nongenotoxic agents that cause pheochromocytomas in rats may do so indirectly by increasing neurally mediated chromaffin cell turnover. The antagonism between PACAP and NGF suggests that neurotransmitters may supersede growth factors in regulating chromaffin cell proliferation during development by suppressing or co-opting portions of growth factor signaling pathways.
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PMID:Mitogenic and antimitogenic effects of pituitary adenylate cyclase-activating polypeptide (PACAP) in adult rat chromaffin cell cultures. 762 29

Recently the cDNA for two different forms of TNF receptor, with gene products of molecular masses of 60 and 80 kDa, have been cloned. In the present report, we investigated the effects of phorbol ester and dibutyryl cAMP on the regulation of the transcript for each type of TNF receptor in U-937 cells. Our results indicate that exposure of these cells to either phorbol ester or dibutyryl cAMP increases the steady state mRNA levels of the 80 kDa form. This effect is dose- and time-dependent. The induction of the p80 receptor transcript by PMA and dibutyryl cAMP was additive suggesting independent mechanisms of induction. Under identical conditions, both agents failed to induce the transcript for the p60 form of the TNF receptor. As demonstrated by actinomycin D pulse-chase experiment, the mRNA for the p80 receptor was found to be highly stable with an approximate half-life of 16 h. No significant change in the half-life was observed when cells were treated with phorbol ester. The mechanisms by which phorbol ester and dibutyryl cAMP induce the upregulation of p80 receptor mRNA appear to be different. Induction of receptor transcript by cycloheximide suggests the presence of a labile repressor protein. Interestingly, the effect of cycloheximide on the induction of the p80 mRNA was found to be additive with that of dibutyryl cAMP but not with phorbol ester. 1-(5-Isoquinolinylsufonyl)-2-methylpiperazine (H7) and N[2-(methylamino) ethyl]-5-isoquinolinesulfonamide (H-8), inhibitors of protein kinase C and protein kinase A, respectively, both inhibited the phorbol ester-mediated induction of the p80-transcript but not that mediated through dibutyryl cAMP. Since dibutyryl cAMP undergoes intracellular dissociation into cAMP and butyric acid, we found that exposure of cells to sodium butyrate alone could induce p80 mRNA in a dose-dependent manner, thus suggesting the role of histone hyperacetylation. Furthermore forskolin treatment, an intracellular inducer of cAMP, increased the receptor transcript level whereas isobutylmethylxanthine, an inhibitor of phosphodiesterase, had no effect. Interestingly, while the p80 form of the TNF receptor mRNA levels was elevated by both phorbol ester and dibutyryl cAMP, only dibutyryl cAMP increased the TNF binding; phorbol ester treatment decreased the binding activity. Thus, our results demonstrate that the genes for the two forms of TNF receptors are differentially regulated. Furthermore, the mechanism of regulation by PMA differs from that by dibutyryl cAMP.
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PMID:Regulation of two forms of the TNF receptors by phorbol ester and dibutyryl cyclic adenosine 3',5'-monophosphate in human histiocytic lymphoma cell line U-937. 768 79


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