Platelet activating factor-stimulated formation of inositol triphosphate in platelets and its regulation by various agents including Ca2+, indomethacin, CV-3988, and forskolin.
When myo-2-[3H]inositol-labeled rabbit platelets were stimulated with 1 X 10(-9)M sn-3-AGEPC (platelet activating factor) for 5 s, the levels of [3H]inositol monophosphate (IP), [3H]inositol diphosphate (IP2), and [3H]inositol triphosphate (IP3) increased about 1.5-, 3-, and 5-fold, respectively. Formation of these inositol polyphosphates was strikingly independent of extracellular Ca2+. Inactive analogs of sn-3-AGEPC, i.e., lysoGEPC and stereoisomer sn-1-AGEPC, did not cause production of any inositol polyphosphate. Pretreatment of platelets with indomethacin (5 microM) had little effect on this phenomenon. On the other hand, a platelet activating factor antagonist, CV-3988, blocked the AGEPC-stimulated production of radioactive IP, IP2, and IP3. Similarly forskolin, an activator of adenylate cyclase, at 5 microM or above completely abolished AGEPC-induced aggregation, [3H]serotonin secretion, and formation of [3H]inositol polyphosphates. In the light of the emerging role of AGEPC in inflammation, hypotension, and other cardiovascular processes, studies with platelets reported here indicate that forskolin could be a useful tool for manipulating AGEPC responses. It is further concluded that AGEPC-induced formation of inositol polyphosphate is an early response "specific" to AGEPC, mediated via extracellular Ca2+-independent phosphoinositide phosphodiesterase, and could play a role in intracellular Ca2+ mobilization and platelet shape change.
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology*; D005576:Colforsin; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007213:Indomethacin / Q000494:pharmacology*; D015544:Inositol 1,4,5-Trisphosphate; D007295:Inositol Phosphates / Q000096:biosynthesis*; D008954:Models, Biological; D010742:Phospholipid Ethers; D010972:Platelet Activating Factor / Q000097:blood*; D011817:Rabbits; D013403:Sugar Phosphates / Q000096:biosynthesis*; D013844:Thiazoles / Q000494:pharmacology*; D013997:Time Factors
D004224:Diterpenes; D007295:Inositol Phosphates; D010742:Phospholipid Ethers; D010972:Platelet Activating Factor; D013403:Sugar Phosphates; D013844:Thiazoles; D005576:Colforsin; D015544:Inositol 1,4,5-Trisphosphate; C037913:CV 3988; D002118:Calcium; D007213:Indomethacin