Role of phospholipid hydrolysis in the mechanism of toxic cell death by calcium and ionophore A23187

Manganese chloride inhibits the hydrolysis of arachidonate-containing phospholipids stimulated in 3T3 mouse fibroblasts by ionophore A23187 in the presence of extracellular calcium. The inhibition is reduced by increasing extracellular calcium concentrations. Stimulation by A23187 of this phospholipid hydrolysis and cell killing are inhibited at similiar concentrations by (i) manganese chloride or (ii) reduced extracellular calcium. These results indicate an important role for the phospholipid hydrolysis in the mechanism of cell killing by A23187 plus calcium. Analysis of the rates of the two processes indicates that phospholipid hydrolysis triggers cell killing, but it is not itself the membrane permeabilizing step.