Elevation of cAMP, but not cGMP, inhibits thrombin-stimulated tyrosine phosphorylation in human platelets.
Platelets have abundant tyrosine kinase activities, and activation of platelets results in the increased tyrosine phosphorylation of numerous protein substrates. The stimulation of tyrosine phosphorylation elicited by thrombin can be completely inhibited by preincubation with 10nm prostacyclin (PGI2), 1 microM PGD2, or 1mM N2,2'-O-dibutyryl-cAMP. In contrast, incubation of platelets with agents that increase cGMP (sodium nitroprusside or with 1mM 8-Bromo-cGMP) was without effect. The inhibition by prostacyclin was dose dependent, with an IC50 of approximately 3nM, corresponding to the dose range necessary to inhibit other platelet activation processes. These results demonstrate a novel pathway by which agents which raise cAMP may inhibit platelet signal transduction and differential mechanism of action between compounds which raise cAMP and those which elevate cGMP.
Department of Pharmacology, University of CT Health Center, Farmington 06030.
K M
KM
Pumiglia
C K
CK
Huang
M B
MB
Feinstein
D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D003994:Bucladesine / Q000494:pharmacology; D000242:Cyclic AMP / Q000097:blood*; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000097:blood* / Q000494:pharmacology; D011464:Epoprostenol / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008970:Molecular Weight; D009599:Nitroprusside / Q000494:pharmacology; D010750:Phosphoproteins / Q000097:blood / Q000302:isolation & purification; D010766:Phosphorylation; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases / Q000097:blood*; D013917:Thrombin / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000097:blood
D010750:Phosphoproteins; D009599:Nitroprusside; D019000:Phosphotyrosine; C016276:8-bromocyclic GMP; D014443:Tyrosine; D003994:Bucladesine; D011464:Epoprostenol; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; D013917:Thrombin; D006152:Cyclic GMP