Protein prenylcysteine analog inhibits agonist-receptor-mediated signal transduction in human platelets.
Signal transduction components, including the Ras superfamily of low molecular weight GTP-binding proteins and the gamma subunits of heterotrimeric G proteins, are reversibly carboxyl methylated at C-terminal prenylcysteine residues. We have previously shown that the prenylcysteine analog N-acetyl-S-trans,trans-farnesyl-L-cysteine (AFC) inhibits carboxyl methylation of these proteins in human platelets. Here we show that concentrations of AFC that inhibit Ras carboxyl methylation (10-50 microM) also block responses to agonists such as ADP, collagen, arachidonic acid, U46619 (a stable analog of prostaglandin H2), thrombin, and guanosine 5'-[gamma-thio]triphosphate. AFC does not inhibit aggregation induced by effectors such as ionomycin, phorbol 12,13-dibutyrate, and bacterial phospholipase C that bypass G proteins to activate platelets at the level of cytosolic Ca2+ concentration and protein kinase C. These findings indicate that AFC inhibits agonist-receptor-mediated signal transduction in human platelets.
Huzoor-Akbar
Department of Biological Sciences, Ohio University, Athens 45701.
Wang
W
W
Kornhauser
R
R
Volker
C
C
Stock
J B
JB
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D008745:Methylation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D017368:Protein Prenylation / Q000187:drug effects*; D016283:Proto-Oncogene Proteins p21(ras) / Q000187:drug effects / Q000378:metabolism*; D012503:Saponins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013917:Thrombin / Q000494:pharmacology
C079500:N-acetyl-S-geranylcysteine; D011450:Prostaglandin Endoperoxides, Synthetic; D012503:Saponins; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D015759:Ionomycin; D000244:Adenosine Diphosphate; D003094:Collagen; D013917:Thrombin; D019204:GTP-Binding Proteins; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); C068268:N-acetyl-S-farnesylcysteine; D002118:Calcium; D000111:Acetylcysteine