| Insulin inhibits human erythrocyte cAMP accumulation and ATP release: role of phosphodiesterase 3 and phosphoinositide 3-kinase. | |
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MedLine Citation:
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PMID: 20404042 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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In non-erythroid cells, insulin stimulates a signal transduction pathway that results in the activation of phosphoinositide 3-kinase (PI3K) and subsequent phosphorylation of phosphodiesterase 3 (PDE3). Erythrocytes possess insulin receptors, PI3K and PDE3B. These cells release adenosine triphosphate (ATP) when exposed to reduced O(2) tension via a signaling pathway that requires activation of the G protein, Gi, as well as increases in cAMP. Although insulin inhibits ATP release from human erythrocytes in response to Gi activation by mastoparan 7 (Mas 7), no effect on cAMP was described. Here, we investigated the hypothesis that insulin activates PDE3 in human erythrocytes via a PI3K-mediated mechanism resulting in cAMP hydrolysis and inhibition of ATP release. Incubation of human erythrocytes with Mas 7 resulted in a 62 +/- 7% increase in cAMP (n = 9, P < 0.05) and a 306 +/- 69% increase in ATP release (n = 9, P < 0.05), both of which were attenuated by pre-treatment with insulin. Selective inhibitors of PDE3 (cilostazol) or PI3K (LY294002) rescued these effects of insulin. These results support the hypothesis that insulin activates PDE3 in erythrocytes via a PI3K-dependent mechanism. Once activated, PDE3 limits Mas 7-induced increases in intracellular cAMP. This effect of insulin leads, ultimately, to decreased ATP release in response to Mas 7. Activation of Gi is required for reduced O(2) tension-induced ATP release from erythrocytes and this ATP release has been shown to participate in the matching of O(2) supply with demand in skeletal muscle. Thus, pathological increases in circulating insulin could, via activation of PDE3 in erythrocytes, inhibit ATP release from these cells, depriving the peripheral circulation of one mechanism that could aid in the regulation of the delivery of O(2) to meet tissue metabolic need. |
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Authors:
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Madelyn S Hanson; Alan H Stephenson; Elizabeth A Bowles; Randy S Sprague |
Publication Detail:
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Type: In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Experimental biology and medicine (Maywood, N.J.) Volume: 235 ISSN: 1535-3699 ISO Abbreviation: Exp. Biol. Med. (Maywood) Publication Date: 2010 Feb |
Date Detail:
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Created Date: 2010-04-20 Completed Date: 2010-05-04 Revised Date: 2011-07-22 |
Medline Journal Info:
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Nlm Unique ID: 100973463 Medline TA: Exp Biol Med (Maywood) Country: England |
Other Details:
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Languages: eng Pagination: 256-62 Citation Subset: IM |
Affiliation:
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Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St Louis, MO 63104, USA. mhanson@mcw.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Triphosphate
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blood* Adult Chromones / pharmacology Cyclic AMP / blood* Cyclic Nucleotide Phosphodiesterases, Type 3 / blood* Enzyme Inhibitors / pharmacology Erythrocytes / drug effects*, metabolism* Female GTP-Binding Protein alpha Subunits, Gi-Go / blood Humans Insulin / blood, pharmacology* Male Middle Aged Models, Biological Morpholines / pharmacology Oxygen / blood Peptides / pharmacology Phosphatidylinositol 3-Kinases / antagonists & inhibitors, blood* Phosphodiesterase 3 Inhibitors Signal Transduction / drug effects Tetrazoles / pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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HL-64180/HL/NHLBI NIH HHS; HL-89094/HL/NHLBI NIH HHS; R01 HL064180-08/HL/NHLBI NIH HHS; R33 HL089094-02/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Chromones; 0/Enzyme Inhibitors; 0/Mas7 protein, synthetic; 0/Morpholines; 0/Peptides; 0/Phosphodiesterase 3 Inhibitors; 0/Tetrazoles; 11061-68-0/Insulin; 154447-36-6/2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; 56-65-5/Adenosine Triphosphate; 60-92-4/Cyclic AMP; 73963-72-1/cilostazol; 7782-44-7/Oxygen; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 3.1.4.17/Cyclic Nucleotide Phosphodiesterases, Type 3; EC 3.6.5.1/GTP-Binding Protein alpha Subunits, Gi-Go |
| Comments/Corrections | |
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