Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.11 (AMPK)
 12,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mouse Leydig cell androgen production can be acutely stimulated by atrial natriuretic factor (ANF) via cyclic guanosine 3',5'-monophosphate (cGMP). This stimulation can approach that seen with high concentrations of luteinizing hormone (LH) acting via cyclic adenosine 3',5'-monophosphate (cAMP). To assess the potential for synergistic interaction between LH/cAMP and ANF/cGMP Leydig cells were co-exposed to ANF and LH or ANF/cGMP and site/type-selective cAMP analogues. Co-exposure to 1 nM ANF and 1 ng/ml LH elicited a synergistic increase in androgen production. Both 500 microM 8-bromo-cGMP and ANF (1.0-2.5 nM) synergized with cAMP analogues selective for either of the two major isoenzymes of protein kinase A. Phosphodiesterase (PDE) inhibition was not involved as inclusion of a PDE inhibitor only augmented the response. It appears that ANF/cGMP may interact cooperatively with LH/cAMP in the stimulatory control of androgen production in the mouse Leydig cell and that the site of synergistic interaction may be the activation of the cAMP-dependent protein kinase.
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PMID:Interaction between cyclic nucleotide second messenger systems in murine Leydig cells. 166 54

High-affinity antibodies against calmodulin (CaM)-dependent cyclic nucleotide phosphodiesterase and protein phosphatase (calcineurin) were purified and characterized. Rabbit anti-phosphodiesterase antibody did not react with other phosphodiesterases or with the regulatory subunits of cAMP-dependent protein kinase. Affinity-purified goat anti-calcineurin antibody recognized both the 61-kDa catalytic subunit and the 18-kDa Ca2+-binding subunit of the phosphatase. Neither antibody reacted with CaM, several CaM-binding proteins (calmodulin-dependent protein kinase, myosin light chain kinase, fodrin), or other cytosolic proteins from brain. The antibodies were used to compare the cellular localization of these two CaM-dependent enzymes in rat brain. Both calcineurin and phosphodiesterase were found predominantly in nerve cells; however, phosphodiesterase was restricted to very specific neuronal populations. Phosphodiesterase was prominent in the somatic cytoplasm and dendrites of regional output neurons--e.g., cerebellar Purkinje cells and hippocampal and cortical pyramidal cells. The extensive and uniform staining in the dendrites was consistent with postsynaptic localization and suggested an important function for this enzyme in neurons that integrate multiple convergent inputs. Calcineurin was present in virtually all classes of neurons, with immunoreactivity confined primarily to cell bodies. Both diffuse cytoplasmic staining and characteristic punctate staining of cell bodies were observed; the latter suggested compartmentalization of calcineurin at or near the plasma membrane. The results of this study demonstrate that calcineurin and phosphodiesterase are differentially localized in the central nervous system. Thus, the expression and compartmentalization of CaM-binding proteins may be highly regulated and specific for particular differentiated nerve cell types.
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PMID:Differential localization of calmodulin-dependent enzymes in rat brain: evidence for selective expression of cyclic nucleotide phosphodiesterase in specific neurons. 302 62

2'-Phosphodiesterase from NIH 3T3 cells was purified about 530-fold. Treatment of the cell lysate with the cAMP-dependent protein kinase causing the 2'-phosphodiesterase inhibition did not result in phosphorylation of the enzyme itself. The kinase was found to phosphorylate a specific 18-kDa protein, the phosphorylated form of this protein being the inhibitor of 2'-phosphodiesterase.
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PMID:Inhibition of 2'-phosphodiesterase by cAMP-dependent protein kinase. Involvement of phosphorylation of protein inhibitor. 609 39

To investigate the role of cAMP-dependent protein kinase (PKA) and cAMP levels in ATP-dependent mitogenesis, Swiss 3T3 cells were transfected with an expression vector coding for (i) a mutated regulatory subunit of PKA (PKA mutant) or (ii) a yeast low Km cAMP phosphodiesterase gene (PDE mutant). The PKA mutant showed 70% reduced PKA activity. Phosphodiesterase activity increased 2.5-fold in the PDE mutant, leading to a great reduction of cAMP levels stimulated by ATP and other cAMP-increasing agents. The mitogenic responses of PKA and PDE mutants to insulin, epidermal growth factor, or 12-O-tetradecanoylphorbol-13-acetate were not significantly changed. However, the further stimulation by ATP, ADP, and adenosine 5'-(beta,gamma-imido)triphosphate in the presence of these growth factors was reduced by > 80%. Mitogenic effect of prostaglandin E2, forskolin, cholera toxin, or adenosine was inhibited in both mutants. The mitogenic stimulation by dibutyryl cAMP, which is resistant to phosphodiesterase, was inhibited in the PKA mutant, but not in the PDE mutant. A partial reduction of platelet-derived growth factor- or bombesin-stimulated mitogenesis, which involves protein kinase C as well as the cAMP signal, was observed in the mutants. These genetic results confirm pharmacological data on the role of PKA and cAMP levels in mitogenesis due to ATP and other growth factors.
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PMID:Role of adenosine 3':5'-monophosphate-dependent protein kinase and cAMP levels in ATP-dependent mitogenesis in Swiss 3T3 cells. 827 49

In vascular smooth muscle cells (VSMCs) of rat tail artery, prostaglandin E2 (PGE2) inhibited a voltage-dependent, delayed rectifier K channel current (Ik). The inhibition was concentration-dependent, via a receptor-mediated mechanism involving the activation of G protein(s) (Ren et al., 1995). In this study, we show that the PGE2-induced inhibition of Ik was mediated by activation of protein kinase A (PKA) and possibly protein kinase C (PKC). Pretreatment of the cells with cyclic adenosine 3',5'-monophosphothioate Rp-isomer (Rp-cAMPs), an inhibitor of adenosine 3', 5'-cAMP-dependent protein kinase (PKA), almost completely abolished the PGE2-induced inhibition. Forskolin, dibutyryl cAMP (Db-cAMP) and cyclic adenosine 3',5'cyclic monophosphothioate Sp-isomer (Sp-cAMPs), activators of adenylate cyclase and PKA, mimicked the effect of PGE2 on Ik. Phosphodiesterase inhibition by 3-isobutyl-1-methylxanthine did not alter the PGE2-induced inhibition of Ik. Moreover, we also found that phorbol myristate acetate (PMA), a PKC activator, significantly suppressed Ik. Both the kinase inhibitor staurosporine and down-regulation of PKC by prolonged exposure of the cells to PMA blocked the PGE2-induced inhibition of Ik, but had no effects on the forskolin, Db-cAMP or SpcAMP-induced effect on Ik. Pretreatment of the cells with Rp-cAMPs only partially diminished the degree of Ik inhibition evoked by PMA. Assay of cAMP content indicated that both PGE2 and PMA induced cAMP accumulation. These results strongly suggest that the modulation of Ik by PGE2 in rat tail artery VSMCs involves signal transduction through both PKA and PKC activation. The activation of PKC may potentiate the cAMP-PKA stimulation, whereas the cAMP-PKA cascade did not seem to affect the PKC pathway. These observations suggest that "cross talk" between the two second-messenger systems is involved in the mechanisms that mediate the effect of PGE2.
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PMID:The actions of prostaglandin E2 on potassium currents in rat tail artery vascular smooth muscle cells: regulation by protein kinase A and protein kinase C. 861 46

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

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

Phosphodiesterases (PDEs) regulate the local concentration of 3',5' cyclic adenosine monophosphate (cAMP) within cells. cAMP activates the cAMP-dependent protein kinase (PKA). In patients, PDE inhibitors have been linked to heart failure and cardiac arrhythmias, although the mechanisms are not understood. We show that PDE4D gene inactivation in mice results in a progressive cardiomyopathy, accelerated heart failure after myocardial infarction, and cardiac arrhythmias. The phosphodiesterase 4D3 (PDE4D3) was found in the cardiac ryanodine receptor (RyR2)/calcium-release-channel complex (required for excitation-contraction [EC] coupling in heart muscle). PDE4D3 levels in the RyR2 complex were reduced in failing human hearts, contributing to PKA-hyperphosphorylated, "leaky" RyR2 channels that promote cardiac dysfunction and arrhythmias. Cardiac arrhythmias and dysfunction associated with PDE4 inhibition or deficiency were suppressed in mice harboring RyR2 that cannot be PKA phosphorylated. These data suggest that reduced PDE4D activity causes defective RyR2-channel function associated with heart failure and arrhythmias.
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PMID:Phosphodiesterase 4D deficiency in the ryanodine-receptor complex promotes heart failure and arrhythmias. 1621 10

Cyclic nucleotides cAMP and cGMP are part of almost all major cellular signaling pathways. Phosphodiesterases (PDEs) are enzymes that regulate the intracellular levels of cAMP and cGMP. Protein kinase A or cAMP-dependent protein kinase mediates most cAMP effects in the cell. Over the last 25 years, various components of this group of molecules have been involved in human diseases, both genetic and acquired. Lately, the PDEs attract more attention. The pharmacological exploitation of the PDE's ability to regulate cGMP and cAMP, and through them, a variety of signaling pathways, has led to a number of new drugs for diverse applications from the treatment of erectile dysfunction to heart failure, asthma, and chronic obstructive pulmonary disease. We present the abstracts (available online) and selected articles from the proceedings of a meeting that took place at the National Institutes of Health (NIH), Bethesda, MD, June 8-10, 2011.
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PMID:Cyclic AMP, protein kinase A, and phosphodiesterases: proceedings of an international workshop. 2295 1

Huntington's disease (HD) causes motor disturbances, preceded by cognitive impairment, in patients and mouse models. We showed that increased hippocampal cAMP-dependent protein kinase (PKA) signaling disrupts recognition and spatial memories in R6 HD mouse models. However, unchanged levels of hippocampal phosphorylated (p) cAMP-responsive element-binding protein (CREB) suggested unaltered nuclear PKA activity in R6 mice. Here, we extend this finding by showing that nuclear pPKA catalytic subunit (Thr197) and pPKA substrate levels were unaltered in the hippocampus of R6/1 mice. Phosphodiesterases (PDEs) play an important role in the regulation of PKA activity. PDE10A, a cAMP/cGMP dual-substrate PDE, was reported to be restricted to the nuclear region in nonstriatal neurons. Using cell fractionation we confirmed that PDE10A was enriched in nuclear fractions, both in wild-type and R6/1 mice hippocampus, without differences in its levels or intracellular distribution between genotypes. We next investigated whether inhibition of PDE10 with papaverine could improve cognitive function in HD mice. Papaverine treatment improved spatial and object recognition memories in R6/1 mice, and significantly increased pGluA1 and pCREB levels in R6/1 mice hippocampus. Papaverine likely acted through the activation of the PKA pathway as the phosphorylation level of distinct cGMP-dependent kinase (cGK) substrates was not modified in either genotype. Moreover, hippocampal cAMP, but not cGMP, levels were increased after acute papaverine injection. Our results show that inhibition of PDE10 improves cognition in R6 mice, at least in part through increased GluA1 and CREB phosphorylation. Thus, PDE10 might be a good therapeutic target to improve cognitive impairment in HD.
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PMID:PDE10 inhibition increases GluA1 and CREB phosphorylation and improves spatial and recognition memories in a Huntington's disease mouse model. 2357 1


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