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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The C-type natriuretic peptide (10(-7) M) and atrial natriuretic peptide (10(-7) M) enhanced cGMP accumulation by 418 and 83 times the control value, respectively, in osteoblast-like MC3T3-E1 cells. The natriuretic peptide B receptor was assumed to be the major natriuretic peptide receptor. 8-Bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP) activated alkaline phosphatase doubled the activity versus the control value on day 15. Phosphodiesterase activity was not stimulated by the addition of cGMP (1 MicroM). cGMP-dependent protein kinase (G kinase) activity of the supernatant fraction was 25.5 pmol/min/mg protein. The 42 kDa protein band was detected to be phosphorylated by G kinase on SDS-PAGE. These results supported the hypothesis that natriuretic peptides regulate the differentiation of MC3T3-E1 cells through a cGMP-dependent pathway.
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PMID:Effect of cyclic GMP produced by natriuretic peptides on osteoblast-like MC3T3-E1 cells. 898 37

Phosphodiesterases (PDEs) play a critical role in the regulation of intracellular cyclic nucleotide concentration and, consequently, regulate the state of cellular differentiation. We have reported that the Src-selective tyrosine kinase inhibitor, herbimycin A, potentiates luteinizing hormone (LH)-stimulated cAMP accumulation in culture media by ovarian thecal-interstitial cells (TIC; see Taylor, C and Terranova, P.F. (1995) Lipopolysaccharide inhibits rat ovarian thecal-interstitial cell steroid secretion in vitro. Endocrinology 136, 5527-5532). The present study was conducted to investigate the effects of herbimycin, and changes in Src tyrosine kinase activity, on PDE activity in rat TIC an in the mouse TM3 Leydig cell line. Treatment of TIC with herbimycin (1 microM) for 24 h inhibited basal and LH-stimulated PDE activity (approximately 50 and 70%, respectively) and was associated with an increase in cAMP and progesterone accumulation in culture media. Treatment of TM3 cells with herbimycin inhibited PDE activity and increased cAMP accumulation in a dose- and time-dependent manner. TM3 cell cultures challenged with herbimycin had lower Src tyrosine kinase activity than controls (approximately 50%); however, protein kinase A activity was unaffected. TM3 cells stably transfected with a dominant negative Src tyrosine kinase (TM3Srck-) had lower PDE activity than cells transfected with a G418 resistance gene alone (TM3pSV2neo) which served as control cells. Conversely, TM3 cells expressing a temperature-sensitive Src kinase had significantly greater PDE activity at the Src active temperature (35 degrees C; the temperature at which the enzyme is active) than TM3pSV2neo control cells grown at the same temperature. TM3 cell lysates hydrolyzed minimal amounts of cGMP, indicating a cAMP-specific PDE. Phosphodiesterase activity in both TM3 and rat TIC was sensitive to the PDE4-selective inhibitor RO20-1724, indicating the predominant active enzyme is probably a member of the cAMP-specific PDE4 family. From the present data, we conclude that a tyrosine kinase of the Src family may play an important role in regulating phosphodiesterase activity in thecal and Leydig cells, and thus regulate intracellular cAMP and the state of cellular differentiation.
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PMID:Src tyrosine kinase activity in rat thecal-interstitial cells and mouse TM3 Leydig cells is positively associated with cAMP-specific phosphodiesterase activity. 902 67

1. Evidence for a 'putative beta 4-adrenoceptor' originated over 20 years ago when cardiostimulant effects were observed to non-conventional partial agonists. These agonists were originally described as beta 1- and beta 2-adrenoceptor antagonists; however, they cause cardiostimulant effects at much higher concentrations than those required to block beta 1- and beta 2-adrenoceptors. Cardiostimulant effects of non-conventional partial agonists have been observed in mouse, rat, guinea-pig, cat, ferret and human heart tissues. 2. The receptor is expressed in several heart regions, including the sinoatrial node, atrium and ventricle. 3. The receptor is resistant to blockade by most antagonists that possess high affinity for beta 1- and beta 2-adrenoceptors, but is blocked with moderate affinity by (-)-bupranolol and CGP 20712A. 4. The receptor is pharmacologically distinct from the beta 3-adrenoceptor. Micromolar concentrations of beta 3-adrenoceptor agonists have no agonist or blocking activity. The receptor is also resistant to blockade by a beta 3-adrenoceptor-selective antagonist. 5. The receptor mediates increases in cAMP levels and cAMP-dependent protein kinase (PK) A activity in cardiac tissues. Phosphodiesterase inhibition potentiates the positive chronotropic and inotropic effects of non-conventional partial agonists. 6. The receptor mediates hastening of atrial and ventricular relaxation, which is consistent with involvement of a cAMP-dependent pathway. 7. The non-conventional partial agonist (-)-[3H]-CGP 12177A labels the cardiac putative beta 4-adrenoceptor. Non-conventional partial agonists compete for binding with affinities that are closely similar to their agonist potencies. Catecholamines compete for binding in a stereoselective manner with a rank order of affinity of (-)-RO363 > (-)-isoprenaline > (-)-noradrenaline > or = (-)-adrenaline >> (+)-isoprenaline, suggesting that catecholamines can interact with the receptor. 8. The putative beta 4-adrenoceptor appears to be coupled to the Gs-adenylyl cyclase system, which could serve as a guide to its future cloning. Activation of the receptor may plausibly improve diastolic function but could also mediate arrhythmias.
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PMID:Proposal for the interaction of non-conventional partial agonists and catecholamines with the 'putative beta 4-adrenoceptor' in mammalian heart. 931 64

Cytokines secreted by activated macrophages play a role in the development of osteolysis adjacent to prosthetic joints. To determine whether the synthesis of cytokines can be inhibited by pharmacological agents, we studied the role of the cAMP-protein kinase A signal transduction pathway in the synthesis of interleukin-6 and tumor necrosis factor-alpha and examined the effect of potential pharmacological regulators of this pathway in human peripheral blood monocytes stimulated with titanium particles. Dibutyryl cAMP enhanced the synthesis of interleukin-6 by titanium-stimulated monocytes and resulted in a marked increase (maximum, seventyfold) in the synthesis of interleukin-6 even in the absence of titanium particles. However, the active analogs (agonists) of cAMP, dibutyryl cAMP and Sp cAMP, inhibited the production of tumor necrosis factor-alpha by titanium-stimulated monocytes (the maximum effects resulted in complete inhibition), while the cAMP antagonist, Rp cAMP, enhanced the production of tumor necrosis factor-alpha. Additional agents that alter the intracellular levels of cAMP were examined for their effects on the synthesis of cytokines. Prostaglandins E1 and E2 were potent inhibitors of the synthesis of tumor necrosis factor-alpha but stimulated the synthesis of interleukin-6. In contrast, indomethacin enhanced the stimulatory effects of titanium particles on tumor necrosis factor-alpha, resulting in a more than threefold increase in the maximum levels of tumor necrosis factor-alpha. Phosphodiesterase inhibitors, such as isobutyryl methylxanthine and pentoxifylline, which increase intracellular levels of cAMP, caused a decrease in the production of tumor necrosis factor-alpha and an increase in the production of interleukin-6. In contrast, the fluoroquinolone antibiotic ciprofloxacin, which is also a phosphodiesterase inhibitor, caused a dose-dependent inhibition of the synthesis of both tumor necrosis factor-alpha and interleukin-6 by titanium-stimulated monocytes, suggesting that ciprofloxacin suppresses the synthesis of interleukin-6 through a mechanism that is independent of cAMP.
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PMID:Modulation of the production of cytokines in titanium-stimulated human peripheral blood monocytes by pharmacological agents. The role of cAMP-mediated signaling mechanisms. 937 38

Mechanisms regulating adipocyte lipolysis are reviewed in three stages. The first stage examines plasma membrane hormone receptors and G-proteins. The primary regulators of adipose tissue lipolysis, the catecholamines, bind to the alpha 2, beta 1, beta 2, and beta 3 adrenergic receptors. The alpha 2 receptor couples with Gi-proteins to inhibit cyclic AMP formation and lipolysis, while the beta receptors couple with Gs-proteins to stimulate cyclic AMP formation and lipolysis. The beta 1 receptor may mediate low level catecholamine stimulation, while the beta 3 receptor, which is activated by higher levels of catecholamines, may deliver a more sustained signal. The second stage examines the regulation of cyclic AMP, the intracellular messenger that activates protein kinase A. Adenylyl cyclase synthesizes cyclic AMP from ATP and is regulated by the G-proteins. Phosphodiesterase 3B hydrolyzes cyclic AMP to AMP and is activated and phosphorylated by both insulin and the catecholamines norepinephrine and epinephrine. The third stage focuses on the rate-limiting enzyme of lipolysis, hormone-sensitive lipase (HSL). This 82 to 88 kDa protein is regulated by reversible phosphorylation. Protein kinase A activates and phosphorylates the enzyme at 2 sites, and 3 phosphatases have been implicated in HSL dephosphorylation. The translocation of HSL from the cytosol to the lipid droplet in response to lipolytic stimulation may be facilitated by a family of lipid-associated droplets called perilipins that are heavily phosphorylated by protein kinase A and dephosphorylated by insulin. As the mechanisms regulating adipocyte lipolysis continue to be uncovered, we look forward to the challenges of integrating these findings with research at the in situ and in vivo levels.
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PMID:Mechanisms regulating adipocyte lipolysis. 978 23

Phosphodiesterase 4D5 is the sole PDE4D cAMP phosphodiesterase isoform expressed in human aortic smooth muscle cells (HASMC). Phorbol 12-myristate 13-acetate (PMA) challenge of HASMC rapidly activated PDE4D5 through a process ablated by the mitogen-activated protein kinase kinase inhibitor PD98059. PMA elicited an inhibitory effect on PDE4D5 activity in HASMC treated with the cyclooxygenase (COX) inhibitor indomethacin, the COX-2 selective inhibitor NS-398, the phospholipase A(2) inhibitor quinacrine, and the cAMP-dependent protein kinase A (PKA) inhibitor H89. PMA challenge of COS-1 cells elicited the rapid inhibition and phosphorylation of both recombinant and endogenous PDE4D5 in a manner ablated by PD98059 and not seen in S651A mutant PDE4D5. PMA promoted the generation of PGE(2) in the medium of HASMC and caused activation of both extracellular signal-regulated kinase (ERK) and PKA through a process ablated by indomethacin, NS-398, quinacrine, and PD98059. Exogenous prostaglandin (PG) E(2) increased cAMP levels and activated PKA in HASMC. COX-2 was expressed in HASMC but not in COS-1 cells. Forskolin challenge of COS-1 cells activated PDE4D5 by causing the PKA-mediated phosphorylation of Ser126 as detected using a novel phosphospecific antiserum. PMA challenge of HASMC elicited phosphorylation of the stimulatory PKA-specific phosphorylation site, Ser126 in PDE4D5 in a manner ablated by PD98059, indomethacin, and H89. We propose that, in HASMC, PMA activates PDE4D5 through an ERK-controlled autocrine mechanism. This involves PGE(2) generation, which causes activation of adenylyl cyclase, allowing PKA to elicit net activation of PDE4D5 by phosphorylation at Ser126.
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PMID:Phorbol 12-myristate 13-acetate triggers the protein kinase A-mediated phosphorylation and activation of the PDE4D5 cAMP phosphodiesterase in human aortic smooth muscle cells through a route involving extracellular signal regulated kinase (ERK). 1164 39

Phosphodiesterase 4D (PDE4D), part of the complex cAMP-specific PDE4 family, plays a pivotal role in the regulation of airway smooth muscle relaxation by catalyzing the hydolysis of cAMP. Its gene on chromosome 5q12 encodes 5 splice variants, which show tissue-dependent expression and regulation. The genomic arrangement of PDE4D was determined using in silico methods, and a putative promoter of one of the protein kinase A-activated, long isoforms, PDE4D5 was identified. Promoter-luciferase constructs, transiently transfected into a beta(2) adrenoreceptor-expressing CHO-K1 cell line, were used to demonstrate that the PDE4D5 promoter up-regulated reporter gene expression in response to increased cell cAMP. Site-directed mutagenesis of the cAMP-response element (CRE) at position -201 identified this as the principal component of the mechanism underlying this cAMP responsiveness. In the second part of this study, cAMP-dependent induction of PDE4D5 transcript in primary cultured human airway smooth muscle cells (hASMs) was demonstrated using both qualitative reverse-transcriptase PCR and quantitative real-time PCR. Isolated PDE4D5 isoenzyme activity, measured after selective immunoprecipitation from hASMs, confirmed that this increase in expression led to an up-regulation of functional activity. We present evidence for cAMP-driven PDE4D5 up-regulation in hASMs and suggest a CRE-containing, isoform-specific promoter as the primary mechanism.
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PMID:Cyclic AMP-dependent transcriptional up-regulation of phosphodiesterase 4D5 in human airway smooth muscle cells. Identification and characterization of a novel PDE4D5 promoter. 1212 97

Yessotoxin (YTX) is a novel phycotoxin with an unknown mechanism of action that has been reported as cardiotoxic, when injected, but non-toxic if ingested orally. In this paper, we studied the effect of YTX on adenosine 3',5'-cyclic monophosphate (cAMP) pathway, since this pathway can be a cellular target to this toxin as happens in other diarrhetic toxins. We determined cAMP levels by enzymeimmunoassay and by using the cAMP dye recombinant fluorescein- and rhodamine-labeled protein kinase A, which increases their fluorescence when cAMP levels are increased. In the presence of YTX, and after a transient small increase, cAMP levels were decreased. This effect was Ca(2+) dependent since in a Ca(2+)-free medium YTX increased cAMP levels, but this event was reverted after addition of external calcium. YTX also reverted the increase of cAMP induced by the adenylyl cyclase activator forskolin. These variations in fluorescence units were confirmed when cAMP levels were measured by enzymeimmunoassay, YTX decreases cAMP from 52.81+/-3.66 to 44.53+/-4.5 fmol. Phosphodiesterase (PDE) IV inhibitors, rolipram or etazolate, did not modify the effect of YTX, however, when PDE IV was first inhibited no effect of YTX was observed. On the other hand, the PDE III inhibitor milrinone counteracted the effect of YTX, and a similar effect was observed with the unspecific PDE I inhibitor chlorpromazine. These results point to an effect of YTX on PDE activity. In the presence of YTX, the fluorescent PDE substrate Mant-cAMP, increased its rate of hydrolysis, the same as the PDE from bovine brain increased the hydrolysis of cAMP substrate. In addition, YTX increased interleukin-2 production, which indirectly confirms a decrease in cAMP. Although results show a very complex pattern of responses, due to the interactions and crosstalks between many systems, results suggest that YTX is a PDE activator in the presence of external Ca(2+).
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PMID:Yessotoxin, a novel phycotoxin, activates phosphodiesterase activity. Effect of yessotoxin on cAMP levels in human lymphocytes. 1250 95

Phosphodiesterase-5 (PDE5) and cGMP-dependent protein kinase (PKG) play key roles in cGMP signaling. PDE5 has a catalytic domain (C domain) that hydrolyzes cGMP and a regulatory domain (R domain) that binds cGMP at allosteric sites. We recently demonstrated that in corpus cavernosum, PDE5 concentration exceeds basal cGMP by ~5-fold making it possible that its allosteric sites could bind a significant fraction of the total cellular cGMP. It is hypothesized that the allosteric sites regulate cGMP signaling by sequestering cGMP. At 60 nM cGMP in vitro, which approaches a stimulated concentration of cGMP in rabbit corpus cavernosum, isolated R domain inhibits both cGMP hydrolysis by C domain and activation of PKG (IC50 values of 388 and 100 nM, respectively). Prior phosphorylation of R domain by cyclic nucleotide-dependent protein kinases, which increases its cGMP-binding affinity, also increases its potency for inhibiting both cGMP hydrolysis by C domain and cGMP activation of PKG (IC50 values of 58 and 38 nM, respectively). In rabbit corpus cavernosum, PDE5 concentration (94 nM) exceeds these values. These findings support our hypothesis that physiological concentrations of R domain regulate cGMP signaling by sequestering this nucleotide and that phosphorylation of R domain modulates this effect. This could provide for negative feedback control of cGMP-signaling.
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PMID:Allosteric sites of phosphodiesterase-5 sequester cyclic GMP. 1476 75

Phosphodiesterase (PDE) 7B, a cAMP-specific PDE which is dominantly expressed in striatum, is expected to be involved in dopaminergic signaling in striatal neurons. Here we show, for the first time, the involvement of the dopaminergic signaling pathway in transcriptional activation of rat PDE7B in primary striatal culture. RT-PCR analysis revealed that dopamine, D1 agonist, forskolin and 8-Br-cAMP stimulation potentiated PDE7B transcription in striatal neurons, while D2 agonist failed to activate the PDE7B transcription. Pre-treatment with D1 antagonist abolished the dopamine- or D1 agonist-induced transcriptional activation of PDE7B. The activation of PDE7B transcription by these stimulators was completely ablated by pre-treatment of the cells with a cAMP-dependent protein kinase inhibitor, H-89. RT-PCR using splice variant-specific primers revealed that transcription of PDE7B1, but not of other splice variants, was activated by D1 agonist. We determined the putative transcription start site of PDE7B1, a brain-specific splice variant of PDE7B, by 5'-RACE and identified a promoter region of PDE7B1. Sequence analysis of the PDE7B1 promoter revealed the presence of a canonical cAMP-response element at 166 bp upstream of the putative transcription start site. The cAMP-responsiveness of the PDE7B1 promoter was demonstrated by functional promoter analysis using the luciferase reporter system. Deletion and mutation of the cAMP-response element site in the PDE7B1 promoter abolished the forskolin-induced activation of the PDE7B1 promoter activity. Electrophoretic mobility shift assay showed the binding of cAMP-response element binding protein to the PDE7B1 promoter. These data demonstrate the dopamine D1 receptor-mediated transcriptional activation of PDE7B through the cAMP/cAMP-dependent protein kinase/cAMP-response element binding protein pathway in striatal neurons.
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PMID:Transcriptional activation of phosphodiesterase 7B1 by dopamine D1 receptor stimulation through the cyclic AMP/cyclic AMP-dependent protein kinase/cyclic AMP-response element binding protein pathway in primary striatal neurons. 1505 90


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