Epinephrine correction of impaired platelet thromboxane receptor signaling.
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.
Dunlop
P C
PC
Hematology/Oncology Section, Department of Medicine, Veterans Administration Medical Center and University of Minnesota, Minneapolis, Minnesota 55417, USA.
Leis
L A
LA
Johnson
G J
GJ
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*
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