Leptin-mediated activation of human platelets: involvement of a leptin receptor and phosphodiesterase 3A-containing cellular signaling complex

Elbatarny, Hisham S.; Maurice, Donald H.

doi:10.1152/ajpendo.00125.2005

Cited by 71 publications

(52 citation statements)

References 35 publications

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“…Interactions between the N terminus of PDE4 and other proteins appear to be involved in the intracellular localization of these isoforms (37)(38)(39)(40), and previous studies have indicated that the N-terminal hydrophobic domains of PDE3 are involved in intracellular localization in transfected cells at least in part through interactions with other proteins (26,41). Several proteins that bind to PDE3 isoforms have been identified recently, but their role in the compartmentation of these enzymes remains unknown (42,43). Experiments designed to identify the mechanisms by which the N-terminal domains regulate the intracellular localization of these isoforms constitute an important direction for future studies.…”

Section: Discussionmentioning

confidence: 99%

Isoforms of Cyclic Nucleotide Phosphodiesterase PDE3 and Their Contribution to cAMP Hydrolytic Activity in Subcellular Fractions of Human Myocardium

Hambleton

Krall

Tikishvili

et al. 2005

Journal of Biological Chemistry

103

104

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Section: Discussionmentioning

confidence: 99%

Isoforms of Cyclic Nucleotide Phosphodiesterase PDE3 and Their Contribution to cAMP Hydrolytic Activity in Subcellular Fractions of Human Myocardium

Hambleton

Krall

Tikishvili

et al. 2005

Journal of Biological Chemistry

103

104

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“…Platelet-rich plasma (PRP) was prepared by centrifugation of heparinized (15 units/ml) blood (284 ϫ g, 15 min at 25°C) and used in aggregation studies as described in ref. 25. Platelets were washed in a Ca 2ϩ -free buffer (0.35% BSA, 137 mM NaCl, 2.7 mM KCl, 11.9 mM NaHCO3, 1 mM MgCl 2, 0.26 mM EGTA, 3 mg/ml apyrase ,and 5 mM Pipes, pH 6.5) and then in this buffer containing 2 mM CaCl 2 and 5 mM Hepes (pH7.4) before being loaded with Fluo-4 A.M. (3 M, 30 min) for use in Ca 2ϩ -release studies.…”

Section: Methodsmentioning

confidence: 99%

Compartmentation and compartment-specific regulation of PDE5 by protein kinase G allows selective cGMP-mediated regulation of platelet functions

Wilson

Elbatarny²,

Crawley³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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It is generally accepted that nitric oxide (NO) donors, such as sodium nitroprusside (SNP), or phosphodiesterase 5 (PDE5) inhibitors, including sildenafil, each impact human platelet function. Although a strong correlation exists between the actions of NO donors in platelets and their impact on cGMP, agents such as sildenafil act without increasing global intra-platelet cGMP levels. This study was undertaken to identify how PDE5 inhibitors might act without increasing cGMP. Our data identify PDE5 as an integral component of a protein kinase G1␤ (PKG1␤)-containing signaling complex, reported previously to coordinate cGMP-mediated inhibition of inositol-1, 4, 5-trisphosphate receptor type 1 (IP 3R1)-mediated Ca 2؉ -release. PKG1␤ and PDE5 did not interact in subcellular fractions devoid of IP 3R1 and were not recruited to IP3R1-enriched membranes in response to cGMP-elevating agents. Activation of platelet PKG promoted phosphorylation and activation of the PDE5 fraction tethered to the IP 3R1-PKG complex, an effect not observed for the nontethered PDE5. Based on these findings, we elaborate a model in which PKG selectively activates PDE5 within a defined microdomain in platelets and propose that this mechanism allows spatial and temporal regulation of cGMP signaling in these cells. Recent reports indicate that sildenafil might prove useful in limiting in-stent thrombosis and the thrombotic events associated with the acute coronary syndromes (ACS), situations poorly regulated with currently available therapeutics. We submit that our findings may define a molecular mechanism by which PDE5 inhibition can differentially impact selected cellular functions of platelets, and perhaps of other cell types.calcium ͉ PKG

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“…by guest www.bloodjournal.org From demonstrated. [12][13][14] Phosphorylated PDE3A has been reported by serine-threonine protein kinase Akt during leptin activation of platelets 15 and in mammalian oocyte maturation. 16 To investigate whether Akt might contribute to thrombin-induced phosphorylation/ activation of PDE3A, we used 3 pharmacologic inhibitors of candidate protein kinases: H89 (a PKA inhibitor), wortmannin (a PI3K inhibitor), and AktI (Akt inhibitor VIII).…”

Section: Thrombin Increases Pde3a Activity Via the Pi3k/akt Pathway Imentioning

confidence: 99%

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

Zhang

Colman

2007

Blood

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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.

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Leptin-mediated activation of human platelets: involvement of a leptin receptor and phosphodiesterase 3A-containing cellular signaling complex

Abstract: Elbatarny, Hisham S., and Donald H. Maurice. Leptin-mediated activation of human platelets: involvement of a leptin receptor and phosphodiesterase 3A-containing cellular signaling complex.

Cited by 71 publications

References 35 publications

Isoforms of Cyclic Nucleotide Phosphodiesterase PDE3 and Their Contribution to cAMP Hydrolytic Activity in Subcellular Fractions of Human Myocardium

Isoforms of Cyclic Nucleotide Phosphodiesterase PDE3 and Their Contribution to cAMP Hydrolytic Activity in Subcellular Fractions of Human Myocardium

Compartmentation and compartment-specific regulation of PDE5 by protein kinase G allows selective cGMP-mediated regulation of platelet functions

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

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