Activation of phospholipase A 2 (PLA 2 ) causing arachidonic acid (AA) release is involved in neuronal cell functions. Previously, we reported AA release and prostaglandin F 2 α (PGF 2 α ) formation via activation of cytosolic PLA 2 by orthovanadate (Na 3 VO 4 ), an inhibitor of tyrosine phosphatases, in rat pheochromocytoma PC12 cells. We investigated the effects of phenylarsine oxide (PAO), which reacts with sulfhydryl groups of proteins and thus acts as an inhibitor of tyrosine phosphatases, on AA release and PGF 2 α formation in PC12 cells. PAO stimulated [ 3 H]AA release from the prelabeled cells and PGF 2 α formation. The PAO responses were dependent upon the concentrations used (10μM to 0.5mM) and on extracellular CaCl 2 . [ 3 H]AA release induced by PAO was decreased significantly by inhibition of secretory, but not cytosolic, PLA 2 . [ 3 H]AA release by PAO was not reversed by washing the cells, but the addition of dithiol compounds such as 2,3-dimercapto-1-propanol decreased the release from the PAO-treated cells. The existence of mRNA of types I B and II C secretory PLA 2 in PC12 cells was detected by reverse transcriptase-polymerase chain reaction using specific primers. Addition of secretory PLA 2 from bee venom to the assay mixture stimulated [ 3 H]AA release, and PAO enhanced the response synergistically. The addition of 0.1mM PAO directly enhanced the activity of secretory PLA 2 from bee venom. These findings suggest that PAO stimulates AA release and PGF 2 α formation probably via activation of secretory PLA 2 in PC12 cells.