Annexin A7 is a ubiquitously expressed Ca(2+)- and phospholipid-binding protein. Erythrocytes from mice lacking annexin A7 (anxA7(-/-)) are deformed and relatively resistant to osmotic swelling. In normal erythrocytes, hyperosmotic shock, Cl(-) removal, and energy depletion (glucose removal) trigger PGE(2) formation, which stimulates Ca(2+)-permeable cation channels, increases cytosolic Ca(2+) activity ([Ca(2+)](i)), and thus triggers suicidal death of erythrocytes or eryptosis, characterized by scrambling of the cell membrane with phosphatidylserine exposure at the cell surface. The present experiments explored the influence of annexin A7 deficiency on eryptosis. In erythrocytes from annexin A7-deficient mice (anxA7(-/-)) and wild-type mice (anxA7(+/+)), PGE(2) formation was determined utilizing an immunoassay, ion channel activity by whole-cell patch clamp recording, [Ca(2+)](i) by fluo3 fluorescence, and phosphatidylserine exposure by binding of annexin A5 in fluorescence activated cell sorter (FACS) analysis. Erythrocyte number and hematocrit were significantly smaller in blood from anx7(-/-) than in anx7(+/+) mice. Cl(-)-removal (replacement with gluconate) stimulated PGE(2)-formation, activated cation currents, increased [Ca(2+)](i), and triggered phosphatidylserine exposure, effects significantly more pronounced in anx7(-/-) than in anx7(+/+) erythrocytes. Hyperosmotic shock (addition of 400 mM sucrose) and glucose depletion (removal of glucose) similarly increased cytosolic Ca(2+) activity and triggered phosphatidylserine exposure, effects again significantly more pronounced in anx7(-/-) than in anx7(+/+) erythrocytes. The effects of Cl(-) removal on PGE(2) formation and the cation current, as well as the effect of hypertonic cell shrinkage on [Ca(2+)](i) and cell membrane scrambling, were blunted following inhibition of cyclooxygenase by aspirin or diclofenac. In conclusion, lack of annexin A7 sensitizes the erythrocytes for "proapoptotic" Ca(2+) overload, an effect shortening the life span of the affected erythrocytes and, thus, leading to anemia.