The effects of lithium on platelet phosphoinositide metabolism

Abstract

The effects on phosphoinositide metabolism of preincubation of platelets for 90 min with 10 mM-Li+ were studied. Measurements were made of [32P]phosphate-labelled phosphoinositides and of [3H]inositol-labelled inositol mono-, bis- and tris-phosphate (InsP, InsP2 and InsP3). (1) Li+ had no effect on the basal radioactivity of the phosphoinositides or in InsP2 or InsP3, but it caused a 1.8-fold increase in the basal radioactivity in InsP. (2) Li+ caused a 4-, 3- and 2-fold enhanced thrombin-induced accumulation of label in InsP, InsP2 and InsP3 respectively. Although the elevated labelling of InsP2 and InsP3 returned to near-basal values within 30-60 min, the high labelling of InsP did not decline over a period of 60 min after addition of thrombin to Li+-treated platelets, consistent with inhibition of InsP phosphatase by Li+. The effect of Li+ was not due to a shift in the thrombin dose-response relationship; increasing concentrations of thrombin enhanced the initial rate of production of radiolabelled inositol phosphates, whereas Li+ affected either a secondary production or the rate of their removal. (3) The only observed effect of Li+ on phosphoinositide metabolism was a thrombin-induced decrease (P < 0.05) in labelled phosphatidylinositol 4-phosphate in Li+-treated platelets; this suggests an effect on phospholipase C. (4) Li+ enhanced (P < 0.05) the thrombin-induced increase in labelled lysophosphatidylinositol, suggesting an effect on phospholipase A2. (5) It was concluded that Li+ inhibits InsP phosphatase and has other effects on phosphoinositide metabolism in activated platelets. The observed effects occur too slowly to be the mechanism by which Li+ potentiates agonist-induced platelet activation.