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)

Sodium orthovanadate (vanadate) stimulated cAMP phosphodiesterase (PDE) and protein tyrosine kinase (PTK) activities and inhibited the phosphotyrosine phosphatase (PTPase) activity in the particulate of isolated rat fat pads. Okadaic acid never showed any increase in the PDE activity up to 1 microM. Amiloride inhibited in part both stimulations of PDE and PTK activities by vanadate. The particulate PTK activity had an optimal divalent ion requirement of 15 mM Mg+2+2 mM Mn+2 in the assay medium and was not inhibited by 1 mM N-ethylmaleimide, suggesting it to be a different type from the insulin receptor and cytosolic PTK activities. The PDE, PTK, and PTPase active fractions were separated from the solubilized particulate fraction on a DEAE-Sephacel column. PDE activity was increased by the addition of the PTK active fraction. A further increase was observed by using the PTK active fraction pretreated with 1 mM vanadate. In contrast, the addition of PTPase active fraction decreased the PDE activity. This decrease disappeared by using the PTPase active fraction pretreated with 1 mM vanadate. These results suggest that the PDE activity is in part regulated through a process involving the particulate PTK and PTPase activities sensitive to vanadate.
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PMID:Regulation of cyclic AMP phosphodiesterase activity by particulate protein tyrosine kinase and phosphotyrosine phosphatase activities sensitive to sodium orthovanadate. 774 86

Involvement of protein kinases in the stimulation of cGMP-inhibited cAMP phosphodiesterase (PDE) activity by orthovanadate (vanadate) was studied. When the fat pads were incubated with 2 mM vanadate or 10 nM insulin, the stimulation of myelin basic protein kinase (MBPK) activity in the particulate by vanadate reached a maximum at 60 min. In contrast, insulin showed a transient increase at 20 min. A 60-min incubation of the fat pads with vanadate stimulated all activities of protein tyrosine kinase (PTK), MBPK, and PDE in the particulate, in a similar dose-dependent manner. Amiloride, a PTK inhibitor, inhibited the stimulations of three enzymes by vanadate in a similar concentration range. Enzyme fractions, which were separated from the solubilized particulate, were subjected to the immunoblot analysis. A fraction of MBPK was identified to contain a major protein of mol wt (44K) and a minor one (42K), both of which are immunoreactive with a mitogen-activated protein kinase (MAPK) antibody. The partially purified PDE activity was stimulated by the addition of the partially purified MBPK. The further stimulation was observed with the PTK-activated MBPK. These results suggest that vanadate stimulates in part the PDE activity through the activation of the particulate MBPK, probably MAPKs, by PTK sensitive to vanadate.
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PMID:Orthovanadate stimulates cyclic guanosine monophosphate-inhibited cyclic adenosine monophosphate phosphodiesterase activity in isolated rat fat pads through activation of particulate myelin basic protein kinase by protein tyrosine kinase. 920 18

The convergence of tyrosine kinase and cyclic AMP (cAMP) signal transduction pathways was investigated in the HT4.7 neural cell line with inhibitors of tyrosine kinases and tyrosine phosphatases. The protein tyrosine kinase inhibitor genistein inhibited isoproterenol-stimulated cAMP production by 40-60% in whole cells, with no effect on basal cAMP levels. In both whole cells and membranes, genistein also inhibited cAMP produced in response to direct stimulation of adenylyl cyclase with forskolin. However, in the absence of phosphodiesterase inhibitors, genistein presentation resulted in an increase in cAMP levels. Genistein inhibited phosphodiesterase activity by 80-85%, indicating that tyrosine phosphorylation stimulates both cAMP synthesis and degradation. The decrease in cAMP levels by genistein was not merely competitive inhibition of adenylyl cyclase with respect to ATP, since the Km of adenylyl cyclase for ATP remained essentially the same in either the presence or the absence of genistein. Another tyrosine kinase inhibitor, herbimycin A, which inhibits by a different mechanism than genistein, also decreased forskolin-stimulated cAMP in whole cells. As would be expected for the involvement of tyrosine phosphorylation in the control of cAMP production, inhibition of tyrosine phosphatases by vandate increased forskolin-stimulated cAMP production. These results suggest that cAMP production can be regulated by tyrosine phosphorylation, and the simultaneous activation of both cAMP synthesis and degradation may serve to alter the duration of cAMP elevation.
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PMID:Modulation of cyclic AMP levels in a clonal neural cell line by inhibitors of tyrosine phosphorylation. 921 88

We have previously shown that the major cAMP phosphodiesterase (PDE) isoforms present in murine thymocytes are the cGMP-stimulated PDE activity (PDE-2) and the cAMP-specific PDE activity (PDE-4), and that these isoforms are differentially regulated following ligation of the TCR (Michie, A.M., Lobban, M. D., Mueller, T., Harnett, M. M., and Houslay, M.D. [1996] Cell. Signalling 8, 97-110). We show here that the anti-CD3-stimulated elevation in PDE-4 activity in murine thymocytes is dependent on protein tyrosine kinase and protein kinase C (PKC)-mediated signals as the TCR-coupled increase in PDE-4 activity can be abrogated by both the tyrosine kinase inhibitor, genistein, and the PKC selective inhibitors chelerythrine and staurosporine. Moreover, the PKC-activating phorbol ester, phorbol-12-myristate, 13-acetate (PMA) caused an increase in PDE-4 activity, similar to that observed in cells challenged with anti-CD3 monoclonal antibodies and which was not additive with cochallenge using anti-CD3 antibodies. Both the PMA- and the anti-CD3 antibody-mediated increases in PDE-4 activity were blocked by treatment with either cycloheximide or actinomycin D. Despite the upregulation of PDE-4 activity consequent to TCR ligation, intracellular cAMP levels increased on challenge of thymocytes with anti-CD3 antibody, indicating that adenylate cyclase activity was also increased by TCR ligation. It is suggested that the anti-CD3-mediated increase in PDE-4 activity was owing to a rapid PKC-dependent induction of PDE-4 activity following crosslinking of the TCR complex. This identifies "crosstalk" occurring between the PKA and PKC signaling pathways initiated by ligation of the antigen receptor in murine thymocytes. That both adenylate cyclase and PDE-4 activities were increased may indicate the presence of compartmentalized cAMP responses present in these cells.
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PMID:Upregulation of cAMP-specific PDE-4 activity following ligation of the TCR complex on thymocytes is blocked by selective inhibitors of protein kinase C and tyrosyl kinases. 951 65

Natural killer (NK) cells are lymphocytes that are capable of destroying tumour cells and virally infected cells (cytolysis) without prior sensitization. When cAMP is artificially elevated in NK cells, it is a potent inhibitor of their cytolytic function. We investigated whether NK-cell cAMP levels are modulated in response to tumour target cells to determine the potential of cAMP as a physiological regulator of NK cytotoxic function. When NK cells are exposed to a range of lysis-sensitive (LS) tumour-target cells there is an increase in intracellular cAMP levels in the NK cells over a 60-min period. The peak increase in cAMP (200-400% above control) occurs at 30 min for all LS targets tested. There is no increase in NK-cell cAMP in response to lysis-resistant (LR) tumour-target cells. The cAMP elevation may be dependent on both LS-target-stimulated adenylyl cyclase (AC) activation and LS-target-stimulated phosphodiesterase (PDE) inhibition. When the NK cells are pretreated with the protein tyrosine kinase (PTK) inhibitor, genistein (30 micrograms/ml), the AC-activation component of the cAMP elevation is abolished. Thus, the AC-activation component appears to require PTK activation. When NK cells are pretreated with the protein kinase C (PKC) inhibitor, chelerythrine chloride (10 microM) the cAMP elevation in response to LS targets was not diminished. This indicates that neither the AC-activation component nor any PDE-inhibition component require PKC activation.
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PMID:Lysis-sensitive targets stimulate an elevation of cAMP in human natural killer cells. 964 Feb 54

In a previous paper we presented evidence for a negative regulation of adenylyl cyclase activity by tyrosine protein kinase(s) in the human leukemic T cell line Jurkat. In order to examine this point in non malignant cells, we conducted the present study in human peripheral blood mononuclear cells (PBMC). In these cells, staurosporine, a broad spectrum protein kinase inhibitor, enhanced not only the receptor-mediated, induced by prostaglandin E2 (PGE2), but also the direct (forskolin-induced) stimulation of adenylyl cyclase activity. Herbimycin A, a specific protein tyrosine kinase inhibitor, reproduced only in part the effect of staurosporine, whereas bisindolylmaleimide, the most specific protein kinase C (PKC) inhibitor known at present time, was ineffective. All these observations were made both in the absence and presence of isobutylmethylxanthine, a phosphodiesterase inhibitor, indicating that the effects of staurosporine and herbimycin A on cAMP accumulation were not due to phosphodiesterase inhibition. The calcium ionophore A 23187 also enhanced the PGE2-induced cAMP accumulation, and this effect was not additive to that of staurosporine, but additive to that of herbimycin A. These results confirm and extend those obtained in Jurkat cells. Taken together, they indicate that in human PBMC the adenylyl cyclase activity is negatively regulated by tyrosine kinase(s) and not by PKC, and positively regulated by Ca2+. They also suggest that the major enhancement by staurosporine of the PGE2-induced cAMP accumulation, although chiefly mediated by protein tyrosine kinase inhibition, also depends on another, presently undetermined, effect of the drug simulating that of Ca2+.
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PMID:Regulation of adenylyl cyclase activity in human peripheral blood mononuclear cells: effects of protein kinase inhibitors and of a calcium ionophore. 981 89

The phosphodiesterase activity in the HT4.7 neural cell line was pharmacologically characterized, and phosphodiesterase isozyme 4 (PDE4) was found to be the predominant isozyme. The Km for cAMP was 1-2 microM, indicative of a "low Km" phosphodiesterase, and the activity was inhibited by PDE4-selective inhibitors rolipram and Ro20-1724, but not PDE3- or PDE2-selective inhibitors. Calcium, calmodulin, and cGMP, regulators of PDE1, PDE2, and PDE3, had no effect on cAMP hydrolysis. The protein tyrosine kinase inhibitor, genistein, inhibited HT4.7 cAMP phosphodiesterase activity by 85-95% with an IC50 of 4 microM; whereas daidzein, an inactive structural analog of genistein, had little effect on phosphodiesterase activity. This is a common pharmacological criterion used to implicate the regulation by a tyrosine kinase. However, genistein still inhibited phosphodiesterase activity with a mixed pattern of inhibition even when ion-exchange chromatography was used to partially purify phosphodiesterase away from the tyrosine kinase activity. Moreover, tyrphostin 51, another tyrosine kinase inhibitor, was found to also inhibit partially purified phosphodiesterase activity noncompetitively. These data suggest that HT4.7 phosphodiesterase activity is dominated by PDE4 and can be regulated by genistein and tyrphostin 51 by a tyrosine kinase-independent mechanism.
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PMID:Tyrosine kinase-independent inhibition of cyclic-AMP phosphodiesterase by genistein and tyrphostin 51. 1035 87

Pentoxifylline (PTF), a phosphodiesterase (PDE) inhibitor, can prevent inflammation and tissue damage in animal and in vitro human studies. However, the underlying mechanism remains unclear. Since Ca2+ is a critical signal regulating the release of inflammatory mediators in macrophages, the effects of PTF on Ca2+ influx were examined in NR8383 alveolar macrophages (AMs). PTF induced a dose-dependent inhibition on Ca2+ influx activated by zymosan and by protein kinase C (PKC) activators 1,2-dioctanoyl-sn-glycerol (DOG) or phorbol-12-myristate 13-acetate (PMA). The inhibition appeared to be specifically on the receptor-operated Ca2+ entry. The capacitative Ca2+ entry was not affected by PTF. The inhibition was not due to altered cAMP levels since the zymosan-activated Ca2+ influx was not affected by the adenylate cyclase activator forskolin, nor by dibutyryl cAMP. Pretreatment with protein tyrosine kinase (PTK) inhibitor genistein abolished zymosan-induced, but not DOG-induced Ca2+ influx, suggesting that PTK is an upstream element of the signaling cascade and not the target of PTF. The Ca2+ entry activated by zymosan and by PKC activators was inhibited by the mitogen-activated protein kinase (MAPK) inhibitor PD98059. Moreover, activation of MAPK by C6-ceramide (C6C) triggered a similar Ca2+ influx as elicited by zymosan and PKC activators, suggesting that MAPK is an element of the pathway. The C6C-induced Ca2+ influx was also inhibited by PTF. These results indicate that PTF blocks the receptor-operated Ca2+ influx in NR8383 AMs by inhibiting PDE which may acts as a downstream element of the signaling pathway or by direct interaction with Ca2+ channels.
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PMID:Inhibition of Ca2+ influx by pentoxifylline in NR8383 alveolar macrophages. 1043 56

Bicarbonate/CO(2), a physiological effector of sperm capacitation, has been shown to induce a rapid and reversible change in the lipid architecture of the plasma membrane of live boar sperm: the change is detectable as an increase in the cells' ability to bind the fluorescent dye merocyanine, a characteristic which implied an increase in lipid packing disorder (Harrison et al. 1996. Mol Reprod Dev 45:378-391). Evidence suggested that cAMP may act as a second messenger in the system, and we have therefore investigated this cAMP-dependency in more detail. Bicarbonate stimulates cAMP levels within 1 min in a dose-dependent fashion, prior to parallel increases in merocyanine binding. Although the potent somatic cell adenylyl cyclase activator forskolin is unable to induce significant increases in cAMP or merocyanine binding, increases in merocyanine binding are inducible in a dose-dependent fashion by 5, 6-dichloro-1-beta-D-ribofuranosylbenzimidazole 3',5'-cyclic monophosphothioate, a cAMP analogue highly specific in its ability to stimulate protein kinase A; moreover, the bicarbonate-induced membrane change is inhibited by H89, a specific protein kinase A inhibitor. Neither bisindolylmaleimide I (protein kinase C inhibitor) nor lavendustin A (protein tyrosine kinase inhibitor) are inhibitory. In the presence of low levels of the potent phosphodiesterase inhibitor papaverine, increases in merocyanine binding are enhanced by okadaic acid and (more effectively) by calyculin (both protein phosphatase inhibitors). We conclude that boar sperm plasma membrane lipid architecture is controlled via a target protein that is dynamically phosphorylated by cAMP-dependent protein kinase and dephosphorylated by protein phosphatase type 1. Mol. Reprod. Dev. 55:220-228, 2000.
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PMID:cAMP-dependent protein kinase control of plasma membrane lipid architecture in boar sperm. 1061 62

Protein tyrosine kinase activity, leading to tyrosine phosphorylation of the intracellular domains of receptors or non-receptor proteins, is an important feature of downstream signalling after receptor binding of a variety factors, such as growth factors and cytokines. Since several members of these classes of paracrine-autocrine mediator may be involved in the intraovarian events of ovulation, the present study was designed to evaluate the effect of protein tyrosine kinase inhibition on the in vitro perfused rat ovary. Immature rats were primed with 20 iu pregnant mares' serum gonadotrophin 48 h before surgical isolation of the right ovary with connecting vasculature. The ovary was placed in a perfusion system for either 10 h, to examine ovarian concentrations of the established ovulatory mediators plasminogen activator, prostaglandins E2 and F2 alpha, or for 20 h, enabling a complete ovulatory process to occur in vitro. Ovulation was induced by ovine LH (0.2 microgram ml-1) in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (0.2 mmol l-1) and the effects of two different protein tyrosine kinase inhibitors, genistein and tyrphostin A25, were studied. Unstimulated control ovaries did not ovulate and showed low secretion of progesterone and oestradiol. Addition of LH + 3-isobutyl-1-methylxanthine resulted in a marked stimulation of steroid release, and ovulations occurred in all ovaries (9.0 +/- 0.9; mean +/- SEM). The protein tyrosine kinase inhibitors, genistein and tyrphostin A25, significantly inhibited ovulation at the higher concentrations tested (3.0 +/- 0.3 at 100 mumol genistein l-1; 5.8 +/- 1.0 at 500 mumol tyrphostin A25 l-1) but no effect was seen at lower concentrations. The presence of genistein and tyrphostin A25 at any concentration used did not significantly decrease the LH + 3-isobutyl-1-methylxanthine-induced progesterone or oestradiol concentrations. The intraovarian concentrations of plasminogen activator activity, and prostaglandin E2 and F2 alpha were not altered by the presence genistein (100 mumol l-1). In conclusion, the results of the present study indicate that protein tyrosine kinase signalling pathways are integral parts of the mammalian ovulatory process but do not involve actions on the synthesis of steroids, plasminogen activator or prostaglandins.
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PMID:Inhibition of ovulation by tyrosine kinase inhibitors in the in vitro perfused rat ovary. 1069 Feb 6


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