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)

Activation of p70s6k in cells stimulated with serum correlates with the phosphorylation of seven sites. Pretreatment of Swiss 3T3 cells with the immunosuppressant rapamycin blocks phosphorylation of four of these sites (Thr229, Thr389, Ser404, and Ser411), whereas phosphorylation proceeds in the remaining three sites (Ser418, Thr421, and Ser424). If rapamycin is added postserum stimulation, the pattern of phosphorylation is qualitatively similar except that Ser411 is still highly phosphorylated. The inhibitory effect of rapamycin on serum-induced p70s6k activation and the phosphorylation of Thr229, Thr389, Ser404, and Ser411 is rescued by FK506, providing further evidence that the inhibitory effect is exerted through a complex of rapamycin-FKBP12. Wortmannin treatment pre- or post-serum stimulation inhibits phosphorylation of the same set of sites as rapamycin, supporting the argument that both agents act on the same pathway. Likewise, methylxanthine phosphodiesterase inhibitors block p70s6k activation and phosphorylation of the same set of sites as wortmannin and rapamycin. However, other agents that raise intracellular cAMP levels have no inhibitory effect, leading to the hypothesis that the inhibitory actions of methylxanthines on p70s6k activity are not through activating protein kinase A but through inhibition of an upstream kinase. Together the results indicate that there are two kinase signaling pathways that must converge to activate p70s6k and that only one of these pathways is sensitive to rapamycin, wortmannin, and methylxanthine inhibition.
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PMID:Rapamycin, wortmannin, and the methylxanthine SQ20006 inactivate p70s6k by inducing dephosphorylation of the same subset of sites. 754 71

The ability of dexamethasone and prednisolone (corticosteroids), FK506 and cyclosporin A (T cell immunosuppressants), and of nitraquazone and rolipram (phosphodiesterase IV inhibitors) to inhibit cytokine production by stimulated human blood was investigated. Heparinized human blood obtained from normal healthy volunteers was stimulated with phytohemagglutinin (PHA) in the presence or absence of drug. After different incubation times, supernatant levels of interleukin (IL)-2, IL-5, granulocyte-macrophage colony stimulating factor (GM-CSF) and interferon gamma (IFN-gamma) were quantified by ELISA. Dexamethasone strongly inhibited the production of IL-5 (IC50 = 0.004 microM), was less potent against IL-2 and IFN-gamma (IC50 = 0.02-0.05 microM) and showed a relatively weak effect against GM-CSF (IC50 = 0.6 microM). Similarly prednisolone potently suppressed IL-5 generation (IC50 = 0.05 microM), displayed a more modest activity on IL-2 and IFn-gamma (IC50 = 0.2-0.3 microM) and exerted only partial effects (43% inhibition at 1 microM) on GM-CSF). FK506 strongly suppressed the production of IL-2 (IC50 = 0.01 microM) and GM-CSF (IC50 = 0.03 microM), but was inactive (< 30% inhibition at 1 microM) against IL-5 and IFN-gamma. Similarly, cyclosporin A reduced the generation of IL-2 (IC50 = 0.4 microM) and GM-CSF (IC50 = 0.6 microM) while barely affecting the other two cytokines. Nitraquazone and rolipram were most active in reducing the production of IL-5 (IC50 = 0.8 and 1.3 microM, respectively), while their potency against IL-2, GM-CSF and IFN-gamma was 3-6 times lower, with IC50's between 2.4 and 8.0 microM. These data indicate that corticosteroids, T cell immunosuppressants and phosphodiesterase IV inhibitors affect cytokine production by PHA-stimulated human blood cells in a differential and "pharmacotypical'' manner.
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PMID:Cytokine production by phytohemagglutinin-stimulated human blood cells: effects of corticosteroids, T cell immunosuppressants and phosphodiesterase IV inhibitors. 884 99

The immunologic and pharmacophysiologic features of atopic dermatitis have stimulated research seeking to identify relevant effector cells and mediators that characterize chronic skin inflammation. The theory that unifies the various abnormalities associated with atopic dermatitis suggests that hematopoietic cells carrying abnormal genetic expressions of atopy cause clinical disease once they infiltrate the skin and mucosa. The proposed underlying mechanism may be either abnormalities in cyclic nucleotide regulation of marrow-derived cells or allergenic overstimulation that causes secondary abnormalities. The primacy of one mechanism over the other remains unresolved, but this does not obviate their value in identifying two novel therapeutic targets: phosphodiesterase inhibition and immune-intervention alternatives to corticosteroids. New type IV phosphodiesterase inhibitors are proving promising in topical formulations, as are inhibitors of calcineurin, such as FK506 and SDZ ASM 981, an ascomycin macrolactam derivative that in early clinical research appears to offer the potency of a corticosteroid without its adverse side effects. The promising clinical trial profiles of these new topical agents may result in alternative therapies providing potent anti-inflammatory activity without the adverse effects that limit corticosteroid use.
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PMID:Biochemical and immunologic mechanisms in atopic dermatitis: new targets for emerging therapies. 1041 15

We have previously reported that varying stimulus intensity produces qualitatively different types of synaptic plasticity in area CA1 of hippocampal slices: brief low-intensity (LI) theta-burst (TB) stimuli induce long-term potentiation (LTP), but if the stimulus intensity is increased (to mimic conditions that may exist during seizures), LTP is not induced; instead, high-intensity (HI) TB stimuli erase previously induced LTP ("TB depotentiation"). We now have explored the mechanisms underlying TB depotentiation using extracellular field recordings with pharmacological manipulations. We found that TB depotentiation was blocked by okadaic acid and calyculin A (inhibitors of serine/threonine protein phosphatases PP1 and PP2A), FK506 (a specific blocker of calcineurin, a Ca(2+)/calmodulin (CaM) protein phosphatase), and 8-Br-cAMP (an activator of protein kinase A) with 3-isobutyl-1-methylxanthine (IBMX, a phosphodiesterase inhibitor). These results suggest that protein phosphatase pathways are involved in the TB depotentiation similar to other type of down-regulating synaptic plasticity such as low-frequency stimulation (LFS)-induced long-term depression (LTD) and depotentiation in the rat hippocampus. However, TB depotentiation and LFS depotentiation could have differential functional significance.
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PMID:Protein phosphatases mediate depotentiation induced by high-intensity theta-burst stimulation. 1257 46

Calcium (Ca(2+)) ions are the currency of heart muscle activity. During excitation-contraction coupling Ca(2+) is rapidly cycled between the cytosol (where it activates the myofilaments) and the sarcoplasmic reticulum (SR), the Ca(2+) store. These fluxes occur by the transient activity of Ca(2+)-pumps and -channels. In the failing human heart, changes in activity and expression profile of Ca(2+)-handling proteins, in particular the SR Ca(2+)-ATPase (SERCA2a), are thought to cause an overall reduction in the amount of SR-Ca(2+) available for contraction. In the steady state, the Ca(2+)-content of the SR is essentially a balance between Ca(2+)-uptake via SERCA2a pump and Ca(2+)-release via the cardiac SR Ca(2+)-release channel complex (Ryanodine receptor, RyR2). This review discusses current pharmacological options available to enhance cardiac SR Ca(2+) content and the implications of this approach as an inotropic therapy in heart failure. Two options are considered: (i) activation of the SERCA2a pump to increase SR Ca(2+)-uptake, and (ii) reduction of SR Ca(2+)-leakage through RyR2. RyR2 forms a macromolecular complex with a number of regulatory proteins that either remain permanently bound or that interact in a time- and/or Ca(2+)-dependant manner. These regulatory proteins can dramatically affect RyR2 function, e.g. over-expression of the accessory protein FK 506-binding protein 12.6 (FKBP12.6) has recently been shown to reduce SR Ca(2+)-leak. Recent attempts to design positive inotropes for chronic administrations have focussed on the use of phosphodiesterase III inhibitors (PDE III inhibitors). These compounds, which increase intracellular cAMP-levels, have failed in clinical trials. Therefore medical researchers are seeking new drugs that act through alternative pathways. Novel cardiac inotropes targeting SR Ca(2+)-cycling proteins may have the potential to fill this gap.
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PMID:Ca(2+)-handling proteins and heart failure: novel molecular targets? 1267 83

Erectile dysfunction is common in male kidney transplant recipients. Interference with the physiology of erections can be attributed to recipient co-morbidities, the renal transplant operation, medication adverse effects, relationship problems and changes in mental health. A treatment-oriented evaluation of erectile dysfunction allows the development of treatment plans that are patient-specific. Hypo-gonadal men whose hormone parameters do not improve after renal transplantation may respond to testosterone replacement therapy. Use of recommended doses of the phosphodiesterase-5 inhibitor sildenafil does not significantly modify trough concentrations of the calcineurin inhibitors ciclosporin and tacrolimus or result in impaired renal allograft function. Tacrolimus has been shown to increase the peak concentration and prolong the elimination half-life of sildenafil in kidney transplant recipients. Daily administration of sildenafil has resulted in decreased blood pressure in kidney transplant recipients with treated hypertension and tacrolimus immunosuppression. Intracavernosal injections of alprostadil, with or without papaverine and phentolamine, are effective treatments for erectile dysfunction after renal transplantation and have not resulted in alterations of ciclosporin concentrations or in deterioration of renal function. Penile prostheses can be successfully implanted after pelvic organ transplantation without significant risk of infection.
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PMID:Treating erectile dysfunction in renal transplant recipients. 1748 43

Ryanodine receptors (RyRs)/Ca2+ release channels, on the endoplasmic and sarcoplasmic reticulum of most cell types, are required for intracellular Ca2+ release involved in diverse cellular functions, including muscle contraction and neurotransmitter release. The large cytoplasmic domain of the RyR serves as a scaffold for proteins that bind to and modulate the channel's function and that comprise a macromolecular signaling complex. These proteins include calstabins [FK506-binding proteins (FKBPs)], calmodulin (CaM), phosphodiesterase, kinases, phosphatases, and their cognate targeting proteins. This review focuses on recent progress in the understanding of RyR regulation and disease mechanisms that are associated with channel dysfunction.
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PMID:Modulation of the ryanodine receptor and intracellular calcium. 1750 40

The role protein phosphatase 2B (calcineurin, CaN) plays in learning and memory has received a significant amount of attention due to its promotion of the dephosphorylation of 3'-5'-cyclic AMP response element binding protein (CREB). Researchers have ascertained that overexpression of CaN is associated with memory retention deficits [Foster TC, Sharrow KM, Masse JR, Norris CM, Kumar A (2001) Calcineurin links Ca(2+) dysregulation with brain aging. J Neurosci 21:4066-4073; Mansuy IM, Mayford M, Jacob B, Kandel ER, Bach ME (1998) Restricted and regulated overexpression reveals calcineurin as a key component in the transition from short-term to long-term memory. Cell 92:39-49], while CaN inhibition enhances learning and memory [Gerdjikov TV, Beninger RJ (2005) Differential effects of calcineurin inhibition and protein kinase A activation on nucleus accumbens amphetamine-produced conditioned place preference in rats. Eur J Neurosci 22:697-705; Ikegami S, Inokuchi K (2000) Antisense DNA against calcineurin facilitates memory in contextual fear conditioning by lowering the threshold for hippocampal long-term potentiation induction. Neuroscience 98:637-646]. The present study hypothesized that infusion of a CaN inhibitor (FK506) bilaterally into the olfactory bulbs of postnatal day 6 Sprague Dawley rat pups would prolong the duration of a conditioned odor preference and retard cyclic AMP response element binding protein dephosphorylation. A 2 mg/kg s.c. injection of isoproterenol (ISO, beta-adrenoceptor agonist) was paired with a 10 min exposure to peppermint and subsequently an infusion of FK506. Immunohistochemistry for phosphorylated 3'-5'-cyclic AMP response element binding protein (pCREB) revealed that unilateral infusion of FK506 resulted in an amplification of phosphorylated CREB in the olfactory bulb 40 min after training compared with saline-infused bulbs. Pups infused bilaterally with FK506 maintained a learned preference for peppermint 48, 72 and 96 h after training. CaN inhibition also modified the conventional inverted U curve obtained when ISO is used to replace stroking, as the unconditioned stimulus. When pups were infused with FK506, learning occurred with sub- and supra-optimal doses of ISO indicating that CaN overcomes non-optimal effects ISO may have on learning. We demonstrate that CaN inhibition can extend the duration of conditioned olfactory memory and may provide a target for memory prolongation that is superior to even phosphodiesterase inhibition observed in previous studies.
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PMID:Calcineurin inhibition eliminates the normal inverted U curve, enhances acquisition and prolongs memory in a mammalian 3'-5'-cyclic AMP-dependent learning paradigm. 1904 26

Calcineurin is a widely expressed and highly conserved Ser/Thr phosphatase. Calcineurin is inhibited by the immunosuppressant drug cyclosporine A (CsA) or tacrolimus (FK506). The critical role of CsA/FK506 as an immunosuppressant following transplantation surgery provides a strong incentive to understand the phosphatase calcineurin. Here we uncover a novel regulatory pathway for cyclic AMP (cAMP) signaling by the phosphatase calcineurin which is also evolutionarily conserved in Caenorhabditis elegans. We found that calcineurin binds directly to and inhibits the proteosomal degradation of cAMP-hydrolyzing phosphodiesterase 4D (PDE4D). We show that ubiquitin conjugation and proteosomal degradation of PDE4D are controlled by a cullin 1-containing E(3) ubiquitin ligase complex upon dual phosphorylation by casein kinase 1 (CK1) and glycogen synthase kinase 3beta (GSK3beta) in a phosphodegron motif. Our findings identify a novel signaling process governing G-protein-coupled cAMP signal transduction-opposing actions of the phosphatase calcineurin and the CK1/GSK3beta protein kinases on the phosphodegron-dependent degradation of PDE4D. This novel signaling system also provides unique functional insights into the complications elicited by CsA in transplant patients.
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PMID:Evolutionarily conserved role of calcineurin in phosphodegron-dependent degradation of phosphodiesterase 4D. 2064 44

The common single nucleotide polymorphism (SNP) rs1360780 (C/T) of the FK506 Binding Protein 5 (FKBP5) gene has been reported to be associated with an altered response of the hypothalamic-pituitary-adrenal (HPA) axis and the development of stress-related psychiatric disorders such as posttraumatic stress disorder (PTSD). In the present study, we examined whether this SNP is associated with cognitive function in a non-clinical population. The full versions of the Wechsler Memory Scale-Revised and Wechsler Adult Intelligence Scale-Revised were administered to 742 and 627 Japanese individuals, respectively, followed by genotyping of rs1360780 by the TaqMan 5'-exonuclease allelic discrimination assay. For both cognitive tests, we found significantly poorer attention/concentration (working memory) in aged (>50 years old) individuals carrying the T allele compared with their counterparts. This finding accords with an altered HPA axis and vulnerability to stress-related psychiatric disorders.
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PMID:The common functional FKBP5 variant rs1360780 is associated with altered cognitive function in aged individuals. 2533 39


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