cAMP-mediated phosphorylation of the low-Km cAMP phosphodiesterase markedly stimulates its catalytic activity.

Grant, Paul G.; Mannarino, Anthony P.; Colman, Robert W.

doi:10.1073/pnas.85.23.9071

Cited by 79 publications

(44 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PKA activation of PDE3 (43)(44)(45)(46) and PDE4 (17, 46 -48) has been well characterized in vitro, although the evidence for this in the heart remains scarce (49,50). Here, while ISO and L-85 clearly enhanced the total PDE3 and PDE4 activities, these effects were not blocked by H89 (Fig.…”

Section: Discussionmentioning

confidence: 78%

Negative Feedback Exerted by cAMP-dependent Protein Kinase and cAMP Phosphodiesterase on Subsarcolemmal cAMP Signals in Intact Cardiac Myocytes

Rochais

Vandecasteele

Lefebvre

et al. 2004

Journal of Biological Chemistry

131

141

View full text Add to dashboard Cite

Intracardiac cAMP levels are modulated by hormones and neuromediators with specific effects on contractility and metabolism. To understand how the same second messenger conveys different information, mutants of the rat olfactory cyclic nucleotide-gated (CNG) channel ␣-subunit CNGA2, encoded into adenoviruses, were used to monitor cAMP in adult rat ventricular myocytes. CNGA2 was not found in native myocytes but was strongly expressed in infected cells. In whole cell patchclamp experiments, the forskolin analogue L-858051 (L-85) elicited a non-selective, Mg 2؉ -sensitive current observed only in infected cells, which was thus identified as the CNG current (I CNG ). The ␤-adrenergic agonist isoprenaline (ISO) also activated I CNG , although the maximal efficiency was Ϸ5 times lower than with L-85. However, ISO and L-85 exerted a similar maximal increase of the L-type Ca 2؉ current. The use of a CNGA2 mutant with a higher sensitivity for cAMP indicated that this difference is caused by the activation of a localized fraction of CNG channels by ISO. cAMP-dependent protein kinase (PKA) blockade with H89 or PKI, or phosphodiesterase (PDE) inhibition with IBMX, dramatically potentiated ISO-and L-85-stimulated I CNG . A similar potentiation of ␤-adrenergic stimulation occurred when PDE4 was blocked, whereas PDE3 inhibition had a smaller effect (by 2-fold). ISO and L-85 increased total PDE3 and PDE4 activities in cardiomyocytes, although this effect was insensitive to H89. However, in the presence of IBMX, H89 had no effect on ISO stimulation of I CNG . This study demonstrates that subsarcolemmal cAMP levels are dynamically regulated by a negative feedback involving PKA stimulation of subsarcolemmal cAMP-PDE.Recent evidence indicates that multimolecular signaling complexes between cell surface receptors and intracellular targets are essential for the speed and specificity of signal transduction events (1, 2, 3). However, how such modules maintain specificity when small diffusible molecules are generated during the signaling cascade is difficult to investigate. This question is particularly relevant for cAMP in the heart, where this cyclic nucleotide second messenger exerts diverse effects in response to a number of different neuromediators and hormones. For instance, the ␤-adrenergic agonist isoprenaline (ISO), 1 prostaglandin E 1 (PGE 1 ), and glucagon-like peptide 1 (GLP-1) elevate intracardiac cAMP levels with different effects on contractility; ISO augments the force of contraction, PGE 1 does not, and GLP-1 exerts a negative inotropic effect (4, 5). In order to explain these results, subcellular compartmentation of cAMP was proposed more than 20 years ago (6).Localized cAMP signals may be generated by the interplay between discrete production sites and restricted diffusion within the cytoplasm. In addition to specialized membrane structures that may circumvent cAMP spreading (6, 7), degradation of cAMP into 5Ј-AMP by cyclic nucleotide phosphodiesterases (PDEs) appears critical for the formation of dynamic microdomain...

show abstract

Section: Discussionmentioning

confidence: 78%

Negative Feedback Exerted by cAMP-dependent Protein Kinase and cAMP Phosphodiesterase on Subsarcolemmal cAMP Signals in Intact Cardiac Myocytes

Rochais

Vandecasteele

Lefebvre

et al. 2004

Journal of Biological Chemistry

131

141

View full text Add to dashboard Cite

show abstract

“…An increased permeability was noted at low concentrations of rolipram (10-7 M), zardaverine ( 10-6 M), or zardaverine (10-9 M)/PGE,. This phenomenon may be related to the known protein kinase A induced phosphorylation and activation of PDE III (33,34); in the presence of low concentrations of a PDE IV or PDE III/IV inhibitor the activity ofthe cAMPdependent protein kinase will increase. PDE III, one target of this reaction, will increase its activity, thereby enhancing overall endothelial cAMP hydrolyzing capacity.…”

Section: Resultsmentioning

confidence: 99%

Role of phosphodiesterases in the regulation of endothelial permeability in vitro.

Suttorp¹,

Weber²,

Welsch³

et al. 1993

J. Clin. Invest.

176

143

View full text Add to dashboard Cite

Neutrophil-derived hydrogen peroxide (H202) is believed to play an important role in the pathogenesis of vascular injury and pulmonary edema. H202 time-and dose-dependently increased the hydraulic conductivity and decreased the selectivity of an endothelial cell monolayer derived from porcine pulmonary arteries. Effects of H202 on endothelial permeability were completely inhibited by adenylate cyclase activation with 10-12 M cholera toxin or 0.1 juM forskolin. 10' M Sp-cAMPS, a cAMP-dependent protein kinase A agonist, was similarly effective. The phosphodiesterase (PDE) inhibitors motapizone (10'-M), rolipram (10-' M), and zardaverine (10-8 M), which specifically inhibit PDE-isoenzymes III, IV, and III/IV potently blocked H202-induced endothelial permeability when combined with 10' M prostaglandin El. Overall cellular cAMP content and inhibition of H202 effects on endothelial permeability were poorly correlated. H202 exposure resulted in a rapid and substantial decrease in endothelial cAMP content. The analysis of the PDE isoenzyme spectrum showed high activities of isoenzymes II, III, and IV in porcine pulmonary endothelial cells. The data suggest that adenylate cyclase activation/PDE inhibition is a powerful approach to block H202-induced increase in endothelial permeability. This concept appears especially valuable when endothelial PDE isoenzyme pattern and PDE inhibitor profile are matched optimally. (J.

show abstract

“…[6][7][8] Phosphorylation of platelet PDE3A by PKA results in activation of PDE3A. To determine whether the activation of PDE3A by thrombin was mediated by phosphorylation, we compared the thrombin-mediated PDE3A activities treated with vehicle or PP1, which removes the phosphate that resulted from stimulation with thrombin.…”

Section: Activation Of Pde3a By Thrombin and A Par-1 Agonistmentioning

confidence: 99%

Thrombin regulates intracellular cyclic AMP concentration in human platelets through phosphorylation/activation of phosphodiesterase 3A

Zhang

Colman

2007

Blood

View full text Add to dashboard Cite

Thrombin-induced cyclic AMP (cAMP) reduction potentates several steps in platelet activation, including Ca ؉؉ mobilization, cytoskeletal reorganization, and fibrinogen receptor conformation. We now reinvestigate the signaling pathways by which intracellular cAMP content is controlled after platelet activation by thrombin. When washed human platelets were stimulated with thrombin, cAMPdependent phosphodiesterase (PDE3A) activity was significantly increased. A nonselective PDE inhibitor, 3-isobutyl-1-methylxanthine (IBMX), and the PDE3 selective inhibitors milrinone and cilostazol each suppressed thrombin-induced cAMP-dependent PDE responses, but not 2 different PDE2 inhibitors. Selective inhibition of PDE3A resulted in reversal of thrombin-induced cAMP reduction, indicating that thrombin activated PDE3A. In synergy with inhibition of adenylate cyclase by thrombin, activated PDE3A accelerates cAMP hydrolysis and maximally reduces the cAMP content. Thrombininduced PDE3A activation was diminished concomitantly with dephosphorylation of PDE3A by protein phosphatase 1 (PP1). An Akt inhibitor blocked PDE3A activation and constrained thrombininduced cAMP reduction. A P2Y 12 inhibitor also reduced thrombin-induced cAMP reduction. The combination of both reversed cAMP decrease by thrombin. Thrombin-mediated phosphorylated PDE3A was isolated by liquid chromatography, detected by a monoclonal antibody against Akt-phosphorylated substrate, and verified by immunoprecipitation study. The predominant isoform phosphorylated by Akt was the 136-kDa species. We suggest that activation/ phosphorylation of PDE3A via Akt signaling pathway participates in regulating cAMP during thrombin activation of platelets.

show abstract

cAMP-mediated phosphorylation of the low-Km cAMP phosphodiesterase markedly stimulates its catalytic activity.

Cited by 79 publications

References 32 publications

Negative Feedback Exerted by cAMP-dependent Protein Kinase and cAMP Phosphodiesterase on Subsarcolemmal cAMP Signals in Intact Cardiac Myocytes

Negative Feedback Exerted by cAMP-dependent Protein Kinase and cAMP Phosphodiesterase on Subsarcolemmal cAMP Signals in Intact Cardiac Myocytes

Role of phosphodiesterases in the regulation of endothelial permeability in vitro.

Thrombin regulates intracellular cyclic AMP concentration in human platelets through phosphorylation/activation of phosphodiesterase 3A

Contact Info

Product

Resources

About