PGE2 in the regulation of programmed erythrocyte death

Abstract

Hyperosmotic shock, energy depletion, or removal of extracellular Cl- activates Ca2+ -permeable cation channels in erythrocyte membranes. Subsequent Ca2+ entry induces erythrocyte shrinkage and exposure of phosphatidylserine (PS) at the erythrocyte surface. PS-exposing cells are engulfed by macrophages. The present study explored the signalling involved. Hyperosmotic shock and Cl- removal triggered the release of prostaglandin E2 (PGE2). In whole-cell recording, activation of the cation channels by Cl- removal was abolished by the cyclooxygenase inhibitor diclophenac. In FACS analysis, phospholipase-A2 inhibitors quinacrine and palmitoyltrifluoromethyl-ketone, and cyclooxygenase inhibitors acetylsalicylic acid and diclophenac, blunted the increase of PS exposure following Cl- removal. PGE2 (but not thromboxane) induced cation channel activation, increase in cytosolic Ca2+ concentration, cell shrinkage, PS exposure, calpain activation, and ankyrin-R degradation. The latter was attenuated by calpain inhibitors-I/II, while PGE2-induced PS exposure was not. In conclusion, hyperosmotic shock or Cl- removal stimulates erythrocyte PS exposure through PGE2 formation and subsequent activation of Ca2+-permeable cation channels. © 2005 Nature Publishing Group All rights reserved.