Effects of fatty acids on activity of cGMP-stimulated cyclic nucleotide phosphodiesterase from calf liver

Yamamoto, Toshihiko; Yamamoto, S; Manganiello, Vincent C.; Vaughan, Martha

doi:10.1016/0003-9861(84)90132-2

Cited by 21 publications

(18 citation statements)

References 24 publications

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“…As shown in Supplement Fig. S2, the sigmoidal shape of the PDE2 cAMP hydrolysis curve measured in the presence of cAMP alone predicts experimental results [51–53], and the simulated EC50 concentration (36 µM) agrees with average values from experiments [6,54,55]. As shown in Fig.…”

Section: Resultssupporting

confidence: 76%

Interaction between phosphodiesterases in the regulation of the cardiac β-adrenergic pathway

Zhao

Greenstein

Winslow

2015

Journal of Molecular and Cellular Cardiology

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In cardiac myocytes, the second messenger cAMP is synthesized within the β-adrenergic signaling pathway upon sympathetic activation. It activates Protein Kinase A (PKA) mediated phosphorylation of multiple target proteins that are functionally critical to cardiac contractility. The dynamics of cAMP are also controlled indirectly by cGMP-mediated regulation of phosphodiesterase isoenzymes (PDEs). The nature of the interactions between cGMP and the PDEs, as well as between PDE isoforms, and how these ultimately transduce the cGMP signal to regulate cAMP remains unclear. To better understand this, we have developed mechanistically detailed models of PDEs 1–4, the primary cAMP-hydrolyzing PDEs in cardiac myocytes, and integrated them into a model of the β-adrenergic signaling pathway. The PDE models are based on experimental studies performed on purified PDEs which have demonstrated that cAMP and cGMP bind competitively to the cyclic nucleotide (cN)-binding domains of PDEs 1, 2, and 3, while PDE4 regulation occurs via PKA-mediated phosphorylation. Individual PDE models reproduce experimentally measured cAMP hydrolysis rates with dose-dependent cGMP regulation. The fully integrated model replicates experimentally observed whole-cell cAMP activation-response relationships and temporal dynamics upon varying degrees of β-adrenergic stimulation in cardiac myocytes. Simulations reveal that as a result of network interactions, reduction in the level of one PDE is partially compensated for by increased activation of others. PDE2 and PDE4 exert the strongest compensatory roles among all PDEs. In addition, PDE2 competes with other PDEs to bind and hydrolyze cAMP and is a strong regulator of PDE interactions. Finally, an increasing level of cGMP gradually out-competes cAMP for the catalytic sites of PDEs 1, 2, and 3, suppresses their cAMP hydrolysis rates, and results in amplified cAMP signaling. These results provide insights into how PDEs transduce cGMP signals to regulate cAMP and how PDE interactions affect cardiac β-adrenergic response.

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Section: Resultssupporting

confidence: 76%

Interaction between phosphodiesterases in the regulation of the cardiac β-adrenergic pathway

Zhao

Greenstein

Winslow

2015

Journal of Molecular and Cellular Cardiology

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“…It was assumed that IBMX affects CFTR through inhibition of PDE, although the K i for PDE inhibition is in the micromolar (10-50 µM) range [37]. Indeed, 10 µM IBMX was shown to effectively activate CFTR in cardiac myocytes, presumably through inhibition of PDE [25].…”

Section: Effects Of Pde Inhibitors On Steady-state Forskolin-dependenmentioning

confidence: 99%

Activation of wild-type and ΔF508-CFTR by phosphodiesterase inhibitors through cAMP-dependent and -independent mechanisms

Al‐Nakkash¹,

Hwang²

1999

Pfl�gers Archiv European Journal of Physiology

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The cAMP-dependent activation of the cystic fibrosis transmembrane conductance regulator (CFTR) and its modulation through inhibition of phosphodiesterases (PDE) were studied with the cell-attached patch-clamp technique in Calu-3 cells (expressing endogenous CFTR) and NIH3T3 cells [expressing either wild-type (Wt)-CFTR or DeltaF508-CFTR]. In Calu-3 cells, CFTR current was augmented by increasing concentrations of 8-(4-chlorophenylthio)-adenosine 3', 5'-cyclic monophosphate (CPT-cAMP) and reached a saturating level at >/=60 microM. Varying the forskolin concentration also modulated CFTR activity; 10 microM was maximally effective since supplemental application of 200 microM CPT-cAMP had no additional effect. Activation of CFTR by increasing the cAMP concentration occurs through an increase of the NPo (product of the number of functional channels and the open probability) since the single-channel amplitude remains unchanged. In Calu-3 and NIH3T3-Wt cells, PDE inhibitors, milrinone (100 microM), 8-cyclopentyl-1, 3-dipropylxanthine (CPX, 25 microM), and 3-isobutyl-1-methylxanthine (IBMX, 200 microM), did not enhance CFTR current initially activated with 10 microM forskolin, but each potentiated CFTR activity elicited with a submaximal forskolin concentration (e.g., 100 nM) and prolonged the deactivation of CFTR channel current upon removal of forskolin. Millimolar IBMX increased the NPo of both Wt- and DeltaF508-CFTR even under maximal cAMP stimulation. Quantitatively, these effects of millimolar IBMX on NPo approximate those of genistein, which potentiates the cAMP-dependent CFTR activity via a mechanism that does not involve increases in cellular cAMP. Thus, depending on the concentration, PDE inhibitors may affect CFTR through different mechanisms.

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“…PDE2 was purified to homogeneity from the supernatant fractions of bovine 'heart, adrenal, liver and platelets using a cGMP affinity resin as the critical final purification step (Martins et al 1982;Miot et al 1985;Yamamoto et al 1983). In addition, PDE2 was purified from the particulate fractions of bovine and rabbit brain using detergents or trypsin treatment to liberate the enzymatic activity from the membranes Whalin et al 1988).…”

Section: Cyclic Gmp-stimulated Phosphodiesterases (Pde2)mentioning

confidence: 99%

Cyclic GMP as substrate and regulator of cyclic nucleotide phosphodiesterases (PDEs)

Juilfs¹,

Soderling

Burns

et al.

Reviews of Physiology, Biochemistry and Pharmacology

130

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Effects of fatty acids on activity of cGMP-stimulated cyclic nucleotide phosphodiesterase from calf liver

Cited by 21 publications

References 24 publications

Interaction between phosphodiesterases in the regulation of the cardiac β-adrenergic pathway

Interaction between phosphodiesterases in the regulation of the cardiac β-adrenergic pathway

Activation of wild-type and ΔF508-CFTR by phosphodiesterase inhibitors through cAMP-dependent and -independent mechanisms

Cyclic GMP as substrate and regulator of cyclic nucleotide phosphodiesterases (PDEs)

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