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)

We examined the involvement of cAMP-dependent protein kinase (A kinase)2 in the inhibition by cilostamide, a specific inhibitor of the low Km cAMP-phosphodiesterase (PDE), on 9,11-epithio-11,12-methanothromboxane A2 (STA2)-induced platelet aggregation. For comparative purposes, the PGE1 analogue, 17S-20-dimethyl-trans-delta 2-PGE1 (OP-1206) was used. OP-1206 (IC50 = 18 +/- 0.55 nM) and cilostamide (IC50 = 40 +/- 4.5 nM) were both potent inhibitors of the platelet aggregation induced by STA2 (1 microM). OP-1206 and cilostamide dose-dependently inhibited elevations in intracellular free Ca2+ ([Ca2+]i) caused by STA2. OP-1206 caused an almost complete inhibition of Ca2+ mobilization, but cilostamide did not prevent the STA2-induced elevation in [Ca2+]i to the same extent as OP-1206, even at a high concentration (greater than 200 nM). Cilostamide did not increase the cAMP level at concentrations (5-100 nm) which affected STA2-induced aggregation. OP-1206 significantly increased cAMP contents in platelets, and the degree of aggregation inhibition by OP-1206 appears to be related to the size of increase in cAMP. OP-1206 increased phosphorylation of the 50,000 mol. wt vasodilator-stimulated phosphoprotein, at concentrations of 7.9-79 nM, which inhibited aggregation induced by STA2. Cilostamide treatment resulted in a marginal increase in the 50,000 mol. wt phosphorylation at concentrations (10-100 nM) which completely inhibited the STA2-induced aggregation. (8R*, 9S*, 11S*)-(-)-9-Hydroxy-9-n-hexyloxy-8-methyl-2,3,9,10- tetrahydro-8,11-epoxy-1H, 8H, 11H-2, 7b, 11a-triazadibenzo(a,g)-cycloocta(c,d,e)trinden-1-one (KT-5720), a specific inhibitor of A kinase, not only reversed the inhibition by OP-1206 of STA2-induced platelet aggregation, but also inhibited the OP-1206-induced protein phosphorylation. However, the inhibition by cilostamide of STA2-induced aggregation was not prevented by pretreatment with KT-5720. Inhibition of the STA2-induced aggregation by OP-1206 may be associated with cAMP-dependent protein phosphorylation, while cilostamide may have inhibitory effects on STA2-induced platelet activation through mechanisms other than the activation of A kinase.
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PMID:Inhibition of platelet aggregation by the cAMP-phosphodiesterase inhibitor, cilostamide, may not be associated with activation of cAMP-dependent protein kinase. 132

Rat granulosa cell-derived insulin-like growth factor (IGF) binding proteins (BPs) have been found subject to biphasic dose-dependent regulation by FSH under in vitro circumstances. Since cAMP may play an intermediary role in FSH hormonal action, we have undertaken to characterize the A kinase-mediated regulation of the elaboration of IGFBPs by cultured rat granulosa cells. Treatment with increasing concentrations of prostaglandin E2 or choleragen, both established cAMP-generating agonists, produced biphasic dose-dependent regulation of the release of the major 28-29 kilodalton (kDa) IGFBP species while promoting the release of their minor 24 (and 19) kDa counterparts. Similar effects were noted for other cAMP-generating agonists including vasoactive intestinal peptide and forskolin (a potent activator of adenylate cyclase). Moreover, concomitant treatment with a functionally inert low dose (10(-7) M) of forskolin, substantially potentiated the FSH (10 ng/ml)-mediated inhibition of the elaboration of the 28-29 kDa IGFBPs. Application of decreasing dilutions of the invasive adenylate cyclase toxin of bordetella pertussis (but not of an inactive mutant strain) yielded monophasic dose-dependent modulation of the release of the 28-29 kDa IGFBPs while effecting biphasic regulation of the 24 kDa moiety. Concurrent treatment with 1-methyl-3-isobutylxanthine (a potent inhibitor of cAMP phosphodiesterase activity) at the 10(-4) M level resulted in profound (P < 0.05) inhibition of the (low dose) FSH (3 ng/ml)-supported accumulation of the major 28-29 kDa IGFBP species, an effect associated with modest (2.5-fold) induction (P < 0.05) of the minor 24 kDa IGFBP moiety. Lastly, provision of increasing concentrations of nondegradable lipophilic analogs of cAMP (i.e. (Bu)2cAMP and 8-bromoadenosine cAMP resulted in biphasic dose-dependent modulation of the release of the major 28-29 kDa IGFBP doublet while producing an increase in the accumulation of the minor 24 kDa IGFBP species. Taken together, these observations suggest that the ability of low dose FSH to stimulate and of high dose FSH to inhibit the elaboration of the 28-29 kDa IGFBP species may entail activation of the A-kinase transduction pathway. Similar conclusions appear to apply for the ability of FSH to regulate (albeit at a lower response sensitivity level) the biphasic elaboration of the 24 kDa IGFBP moiety. As such, these observations point out the disparate response sensitivities of distinct IGFBP species, thereby suggesting a novel potent mechanism through which FSH may determine the relative distribution pattern of granulosa cell-derived IGFBPs and the consequent overall IGF responsiveness of this cell type.
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PMID:A kinase-mediated regulation of granulosa cell-derived insulin-like growth factor binding proteins (IGFBPs): disparate response sensitivities of distinct IGFBP species. 768 61

Approximately 88% of the total cAMP phosphodiesterase (PDE) activity was detected in the supernatant fraction of the rat parotid homogenate. Mono Q ion-exchange chromatography revealed five main peaks (PDE I, PDE II, PDE III, PDE IV and unknown). A high concentration of cGMP (> 1 microM) was necessary to activate PDE II, whereas PDE III was inhibited by cGMP at a concentration that was 1,000 times lower (100 pM). PDEs III and IV were activated by treatment with a catalytic subunit of cAMP-dependent protein kinase (A kinase), and H-8, a A kinase inhibitor, inhibited the activation. Treatment of parotid slices with 1 microM isoproterenol stimulated PDE activity by approximately 120%, and 10 microM propranolol inhibited the activation.
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PMID:Regulation of cAMP phosphodiesterases by cyclic nucleotides in rat parotid gland. 874 32

The original model for regulation of oocyte maturation proposed by us in 1978 postulated that gap junction-mediated transmission of cAMP from the follicle cells to the oocyte inhibits meiosis and that luteinizing hormone (LH) terminates the flux of the follicle cAMP to the oocyte. A decrease in oocyte cAMP below inhibitory threshold occurs since oocytes lack the ability to generate sufficient amounts of cAMP to compensate for the phosphodiesterase activity. Our previous studies provided evidence to support this model. More recent studies in our laboratory were directed at identification of the cellular biochemical and molecular events initiated within rat oocytes upon the relief of cAMP inhibition. These studies: (i) identified an oocyte specific A kinase anchoring protein (AKAP) that is phosphorylated in oocytes resuming meiosis, (ii) confirmed that cdc25B governs meiosis reinitiation and demonstrated that its expression is translationally regulated, (iii) substantiated the indispensable role of proteasomal degradation at completion of the first meiotic division in a mammalian system, (iv) elucidated the role of MPF reactivation in suppressing interphase between the two meiotic divisions and (v) provided evidence that mos translation is negatively regulated by a protein kinase A (PKA)-mediated action of cAMP and is dependent on an active MPF. A detailed account on each of these findings is presented in this chapter.
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PMID:Cellular, biochemical and molecular mechanisms regulating oocyte maturation. 1583 49

Following its production by adenylyl cyclases, the second messenger cAMP is in involved in pleiotrophic signal transduction. The effectors of cAMP include the cAMP-dependent protein kinase (PKA), the guanine nucleotide exchange factor Epac (exchange protein activated by cAMP), and cAMP-dependent ion channels. In turn, cAMP signaling is attenuated by phosphodiesterase-catalyzed degradation. The association of cAMP effectors and the enzymes that regulate cAMP concentration into signaling complexes helps to explain the differential signaling initiated by members of the G(s)-protein coupled receptor family. The signal transduction complex formed by the scaffold protein mAKAP (muscle A kinase-anchoring protein) at the nuclear envelope of both striated myocytes and neurons contains three cAMP-binding proteins, PKA, Epac1, and the phosphodiesterase PDE4D3. In addition, the mAKAP complex also contains components of the ERK5 MAP kinase signaling pathway, the calcium release channel ryanodine receptor and the phosphatases PP2A as well as calcineurin. Analysis of the mAKAP complex illustrates how a macromolecular complex can serve as a node in the intracellular signaling network of cardiac myocytes to integrate multiple cAMP signals with those of calcium and MAP kinases to regulate the hypertrophic actions of several hormones.
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PMID:The mAKAP signaling complex: integration of cAMP, calcium, and MAP kinase signaling pathways. 1646 Aug 34

Stimulation of several G-protein-coupled receptors (GPCRs) promotes intracellular production of cyclic adenosine 3',5'-monophosphate (cAMP) and subsequently activates protein kinase A (PKA). In the heart, beta-adrenergic receptor (beta-AR) stimulation increases contractile performance and heart rate as part of the 'fight-or-flight' stress response. Molecular organisation of PKA-effector association occurs by A kinase anchoring proteins (AKAPs), which target kinase action to specific intracellular sites. Some AKAPs interact directly with specific cAMP-hydrolysing phosphodiesterase (PDE) isoforms allowing for the assembly of multi-protein complexes that create focal points of intracellular cAMP signalling. Certain PDE isoforms co-localise with PKA as part of negative feedback mechanisms which may protect from excess beta-AR stimulation of Ca2+ transporters during cardiac excitation-contraction coupling. Pharmacological PDE inhibition increases intracellular cAMP concentrations and augments excitation-contraction coupling in heart failure. However, chronic PDE inhibitor treatment causes severe cardiac side effects and increases mortality. Moreover, cAMP hydrolysing PDE activity was found decreased in heart failure which may contribute to disease progression via chronic PKA-dependent dysregulation of Ca2+ transport proteins. The authors review the contribution of PDE activity in the heart to contractile stress adaptation, the significance of altered cAMP signalling in heart failure, and the effects of PDE inhibition in heart disease.
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PMID:Phosphodiesterase 4D and heart failure: a cautionary tale. 1698 25

Many different receptors can stimulate cAMP synthesis in the heart, but not all elicit the same functional responses. For example, it has been recognized for some time that prostaglandins such as PGE1 increase cAMP production and activate PKA, but they do not elicit responses like those produced by beta-adrenergic receptor (betaAR) agonists such as isoproterenol (isoprenaline), even though both stimulate the same signalling pathway. In the present study, we confirm that isoproterenol, but not PGE1, is able to produce cAMP-dependent stimulation of the L-type Ca(2+) current in guinea pig ventricular myocytes. This is despite finding evidence that these cells express EP(4) prostaglandin receptors, which are known to activate G(s)-dependent signalling pathways. Using fluorescence resonance energy transfer-based biosensors that are either freely diffusible or bound to A kinase anchoring proteins, we demonstrate that the difference is due to the ability of isoproterenol to stimulate cAMP production in cytosolic and caveolar compartments of intact cardiac myocytes, while PGE1 only stimulates cAMP production in the cytosolic compartment. Unlike other receptor-mediated responses, compartmentation of PGE1 responses was not due to concurrent activation of a G(i)-dependent signalling pathway or phosphodiesterase activity. Instead, compartmentation of the PGE1 response in cardiac myocytes appears to be due to transient stimulation of cAMP in a microdomain that can communicate directly with the bulk cytosolic compartment but not the caveolar compartment associated with betaAR regulation of L-type Ca(2+) channel function.
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PMID:cAMP microdomains and L-type Ca2+ channel regulation in guinea-pig ventricular myocytes. 1728 86

Activation of the beta adrenergic receptor (betaAR) induces a tightly controlled cAMP/protein kinase A (PKA) activity to ensure an agonist dose-dependent and saturable contraction response in animal heart. We have found that stimulation of beta(1)AR by isoproterenol induces maximal contraction responses at the dose of 1 microM in cardiac myocytes; however, cAMP accumulation continues to increase with higher agonist concentrations. Dose-dependent cAMP accumulation is tightly controlled by negative regulator phosphodiesterase 4 (PDE4) that hydrolyzes cAMP. At 1 nM isoproterenol, cAMP accumulation is minimal because of the hydrolysis of cAMP by PDE4, which leads to a small increase in PKA phosphorylation of phospholamban and troponin I (TnI), and contraction responses. Inhibition of PDE4 activity with rolipram enhances cAMP accumulation, yields maximal PKA phosphorylation of phospholamban and TnI, and myocyte contraction responses. In contrast, at 10 microM isoproterenol, despite the negative effect of PDE4, cAMP accumulation is sufficient for maximal PKA phosphorylation of phospholamban and TnI. Inhibition of PDE4 with rolipram enhances cAMP accumulation, but not PKA phosphorylation and contraction responses. It is interesting that activities of both PKA and protein phosphatase 2A (PP2A) are enhanced under beta(1)AR activation with 10 microM isoproterenol, and PP2A is recruited to PKA/A kinase-anchoring protein complex. Inhibition of PP2A with okadaic acid further enhances the phosphorylation of phospholamban and TnI as well as contraction responses induced by 10 microM isoproterenol. Therefore, PP2A plays a key role in limiting PKA phosphorylation of phospholamban and TnI for myocyte contraction responses under beta(1)AR stimulation.
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PMID:Phosphodiesterase 4 and phosphatase 2A differentially regulate cAMP/protein kinase a signaling for cardiac myocyte contraction under stimulation of beta1 adrenergic receptor. 1870 69

Numerous cAMP-elevating agents regulate events required for efficient migration of arterial vascular smooth muscle cells (VSMCs). Interestingly, when the impact of cAMP-elevating agents on individual migration-related events is studied, these agents have been shown to have distinct, and sometimes unexpected, effects. For example, although cAMP-elevating agents inhibit overall migration, they promote VSMC adhesion to extracellular matrix proteins and the formation of membrane extensions, which are both events that are essential for and promote migration. Herein, we extend previous observations that identified phosphodiesterase-4D3 (PDE4D3) as an integral component of a PKA/A kinase-anchoring protein (AKAP) complex in cultured/hypertrophied rat cardiac myocytes to the case for nonhypertrophied cardiac myocytes. Moreover, we show that while rat aortic VSMCs also express PDE4D3, this protein is not detected in PKA/AKAP complexes isolated from these cells. In contrast, we show that another PDE4D splice variant expressed in arterial vascular myocytes, namely, PDE4D8, integrates into PKA/AKAP-based signaling complexes in VSMCs. Consistent with the idea that a PDE4D8/PKA/AKAP complex regulates specific VSMC functions, PKA and PDE4D8 were each recruited to leading-edge structures in migrating VSMCs, and inhibition of PDE4D8 recruitment to pseudopodia of migrating cells caused localized changes in actin dynamics. Our data are presented in the context that cardiac myocytes and arterial VSMCs may use distinct PDE4D variants to regulate selected pools of targeted PKA activity and that disruption of this complex may allow selective regulation of cAMP-dependent events between these two cardiovascular cell types.
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PMID:Distinct phosphodiesterase-4D variants integrate into protein kinase A-based signaling complexes in cardiac and vascular myocytes. 1906 Jan 29

The cardiac I(Ks) potassium channel is a macromolecular complex consisting of alpha-(KCNQ1) and beta-subunits (KCNE1) and the A kinase-anchoring protein (AKAP) Yotiao (AKAP-9), which recruits protein kinase A) and protein phosphatase 1 to the channel. Here, we have tested the hypothesis that specific cAMP phosphodiesterase (PDE) isoforms of the PDE4D family that are expressed in the heart are also part of the I(Ks) signaling complex and contribute to its regulation by cAMP. PDE4D isoforms co-immunoprecipitated with I(Ks) channels in hearts of mice expressing the I(Ks) channel. In myocytes isolated from these mice, I(Ks) was increased by pharmacological PDE inhibition. PDE4D3, but not PDE4D5, co-immunoprecipitated with the I(Ks) channel only in Chinese hamster ovary cells co-expressing AKAP-9, and PDE4D3, but not PDE4D5, co-immunoprecipitated with AKAP-9. Functional experiments in Chinese hamster ovary cells expressing AKAP-9 and either PDE4D3 or PDE4D5 isoforms revealed modulation of the I(Ks) response to cAMP by PDE4D3 but not PDE4D5. We conclude that PDE4D3, like protein kinase A and protein phosphatase 1, is recruited to the I(Ks) channel via AKAP-9 and contributes to its critical regulation by cAMP.
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PMID:The cardiac IKs potassium channel macromolecular complex includes the phosphodiesterase PDE4D3. 1921 43


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