title: Epinephrine correction of impaired platelet thromboxane receptor signaling.
abstract: This study evaluated the mechanism of epinephrine potentiation of platelet secretion induced by thromboxane A(2) (TXA(2)). Dog platelets that do not secrete in response to TXA(2) alone (TXA(2)-) were compared with dog platelets that do secrete (TXA(2)+) and with human platelets. TXA(2)- platelets had impaired TXA(2) receptor (TP receptor)-G protein coupling, indicated by 1) impaired stimulated GTPase activity, 2) elevated basal guanosine 5'-O-(3-thiotriphosphate) binding, and 3) elevated Galpha(q) palmitate turnover that was corrected by preexposure to epinephrine. Kinetic agonist binding studies revealed biphasic dog and human platelet TP receptor association and dissociation. TXA(2)- and TP receptor-desensitized TXA(2)+ dog and human platelets had altered ligand binding parameters compared with untreated TXA(2)+ or human platelets. These parameters were reversed, along with impaired secretion, by epinephrine. Basal phosphorylation of TXA(2)- platelet TP receptors was elevated 60% and was normalized by epinephrine. Epinephrine potentiates platelet secretion stimulated by TXA(2) by reducing basal TP receptor phosphorylation and facilitating TP receptor-G protein coupling in TXA(2)- platelets and, probably, in normal platelets as well.
authors.affiliation: Hematology/Oncology Section, Department of Medicine, Veterans Administration Medical Center and University of Minnesota, Minneapolis, Minnesota 55417, USA.
authors.forename: P C
authors.initials: PC
authors.lastname: Dunlop
authors.forename: L A
authors.initials: LA
authors.lastname: Leis
authors.forename: G J
authors.initials: GJ
authors.lastname: Johnson
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D001792:Blood Platelets / Q000201:enzymology; D002250:Carbon Radioisotopes; D004285:Dogs; D004837:Epinephrine / Q000494:pharmacology*; D020558:GTP Phosphohydrolases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D007457:Iodine Radioisotopes; D007700:Kinetics; D008969:Molecular Sequence Data; D009153:Mutagens / Q000378:metabolism / Q000494:pharmacology; D009602:Nitrosamines / Q000378:metabolism / Q000494:pharmacology; D010168:Palmitates / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation; D015539:Platelet Activation / Q000187:drug effects* / Q000502:physiology; D017482:Receptors, Thromboxane / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013462:Sulfur Radioisotopes; D013928:Thromboxane A2 / Q000378:metabolism; D014316:Tritium; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D002250:Carbon Radioisotopes; D007457:Iodine Radioisotopes; D009153:Mutagens; D009602:Nitrosamines; D010168:Palmitates; D017482:Receptors, Thromboxane; D013462:Sulfur Radioisotopes; D014662:Vasoconstrictor Agents; D014316:Tritium; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013928:Thromboxane A2; C013622:nitrosobis(2-oxopropyl)amine; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015544:Inositol 1,4,5-Trisphosphate; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D004837:Epinephrine