The regulation and physiology of membrane phospholipid asymmetry. This model describes how membrane phospholipid asymmetry is generated, maintained, and perturbed as a prerequisite to various phosphatidylserine-related pathophysiologies. Membrane lipid asymmetry is regulated by the cooperative activities of three transporters. The ATP-dependent aminophospholipid-specific translocase, which rapidly transports PS and PE from the cell's outer-to-inner leaflet; the ATP-dependent nonspecific lipid floppase, which slowly transports lipids from the cell's inner-to-outer leaflet; and the Ca²⁺-dependent nonspecific lipid scramblase, which allows lipids to move randomly between both leaflets. The model predicts that the translocases are targets for Ca²⁺ that directly regulates the transporter's activities. The figure shows that elevated intracellular Ca²⁺ induces PS randomization across the cell's plasma membrane by providing a stimulus that positively and negatively regulates scramblase and translocase activities, respectively. At physiologic Ca²⁺ concentrations, PS asymmetry is promoted because of an active translocase and floppase but inactive scramblase. Depending on the type of cell, elevated intracellular Ca²⁺ levels can be achieved by cellular activation that generally results in the concomitant influx and accumulation of extracellular Ca²⁺ and by its release from intracellular stores. Increased cytosolic Ca²⁺ can also result in calpain activation, which facilitates membrane blebbing and the release of PS-expressing procoagulant microvesicles. Exposure of PS at the cell's outer leaflet. The appearance of PS at the cell's outer leaflet promotes coagulation and thrombosis by providing a catalytic surface for the assembly of the prothrombinase and tenase (not shown) complexes and marks the cell as a pathologic target for elimination by phagocytes. Recognition of the PS-expressing targets can occur by both antibody-dependent and direct receptor-mediated pathways. (Aminophospholipids are shown with red polar headgroups and cholinephospholipids with blue polar headgroups, see cover photo; β2-Gp, β2-glycoprotein-I; rec, receptor).