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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Torti, Mauro Lova, Paolo Baldanzi, Gianluca Campus, Francesca Bernardi, Bruno Balduini, Cesare Guidetti, Gianni F. Graziani, Andrea |
| Description | Author Affiliation: Guidetti GF ( Center of Excellence for Applied Biology, Department of Biochemistry, University of Pavia, via Bassi 21, 27100 Pavia, Italy.) |
| Abstract | Stimulation of G(q)-coupled receptors activates phospholipase C and is supposed to promote both intracellular Ca(2+) mobilization and protein kinase C (PKC) activation. We found that ADP-induced phosphorylation of pleckstrin, the main platelet substrate for PKC, was completely inhibited not only by an antagonist of the G(q)-coupled P2Y1 receptor but also upon blockade of the G(i)-coupled P2Y12 receptor. The role of G(i) on PKC regulation required stimulation of phosphatidylinositol 3-kinase rather than inhibition of adenylyl cyclase. P2Y12 antagonists also inhibited pleckstrin phosphorylation, Rap1b activation, and platelet aggregation induced upon G(q) stimulation by the thromboxane A(2) analogue U46619. Importantly, activation of phospholipase C and intracellular Ca(2+) mobilization occurred normally. Phorbol 12-myristate 13-acetate overcame the inhibitory effect of P2Y12 receptor blockade on PKC activation but not on Rap1b activation and platelet aggregation. By contrast, inhibition of diacylglycerol kinase restored both PKC and Rap1b activity and caused platelet aggregation. Stimulation of P2Y12 receptor or direct inhibition of diacylglycerol kinase potentiated the effect of membrane-permeable sn-1,2-dioctanoylglycerol on platelet aggregation and pleckstrin phosphorylation, in association with inhibition of its phosphorylation to phosphatidic acid. These results reveal a novel and unexpected role of the G(i)-coupled P2Y12 receptor in the regulation of diacylglycerol-mediated events in activated platelets. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 43 |
| Volume Number | 283 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2008-10-24 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Blood Platelets Metabolism Diglycerides GTP-Binding Protein Alpha Subunits, Gi-Go Receptors, Purinergic P2 Signal Transduction 15-Hydroxy-11 Alpha,9 Alpha-(epoxymethano)prosta-5,13-dienoic Acid Pharmacology Adenosine Diphosphate Chemistry Blood Proteins Diacylglycerol Kinase Enzyme Inhibitors Phosphoproteins Platelet Aggregation Platelet Aggregation Inhibitors Protein Kinase C Receptors, Purinergic P2Y12 Thromboxane A2 Research Support, Non-U.S. Gov't Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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