Human platelets possess a specific membrane-bound leukotricnc (LT) C., synlhase, which catalyzes the conversion of LTA, to LTC,. Sti tnulation of the rcccptoi-s for thronibin, collagen or thromboxane A, provoked inhibition of this cnzyme, as judged by suppressed trmsformation of exogenous LTA, to LTC,.Similarly, direct activation of protein kinase (PK) C with riiltiomolur concentrations of 4/1-phorhol 12-myristate 13-acelate (PMA) inhibited the production of I,TC:,. Kinetic studies demonstrated that the i nhibition induced by thrombin and PMA was nori-compctitive. Elevation of inlracellular CAMP levels with carbacyclin did not affect basal LTC, formation, hut abolished the attenuation d' platelet LTC, synthasc activity induced by the thromboxane receptor agonisl U-46619. The unselective prolein kinasc inhibitor lstaurosporine prevented both receptor-mediated and PMA-induced suppression of LTC, formation. In contrast, two selective PKC inhibitors, Ro 31 4 2 2 0 and GF 100203X, reversed the inhibitory effect provoked by PMA, but failed to prevent thrombin-induced inhibition, Furthermore, the protein tyrosine phosphatase inhibitor, sodium orthovanadate, induced dose-dependent inhibition of LTC, production in platelet sonicates. In conclusion, receptor-mediated activation u f human platclets leads to decreased I,TC:., synthase activity via phosphoregulation. Although the present results demonstrate that platelet LIC, synthase can be regulated via PKC-dependent events, alternative mechanisms appears to be involved in the physiological regulation of this enzyme. The findings suggcst the possible importance of protein tyrosine phophorylations in this process.