Biol. Pharm. Bull. 29(8) 1542—1546 (2006)

Lipids of the plasma membrane are distributed asymmetrically between two leaflets, and the presence of glycerophospholipids and sphingolipids contribute to this asymmetry (Fig. 1). Of the glycerophospholipids, phosphatidylcholine (PC) is located mainly in the outer (extracytosolic) leaflet, and the aminophospholipids phosphatidylserine (PS) and phosphatidylethanolamine (PE), as well as minor lipids like phosphatidylinositol (PI) and phosphatidic acid (PA), are abundant in the inner (cytosolic) leaflet. The sphingolipids, sphingomyelin (SM) and glycosphingolipids, are confined to the outer leaflet. Translocation of lipids from one leaflet to the other is called ‘flip-flop’, with ‘flip’ being the movement from the extracytosolic leaflet to cytosolic leaflet, and ‘flop’ being the reverse. Since the polar head groups of glycerophospholipids and sphingolipids make it difficult for them to traverse the hydrophobic interior membrane, spontaneous transbilayer movement is very slow in protein-free model membranes. Therefore, the existence of enzymes that catalyze transbilayer movement, called lipid translocases or flippases, has been assumed. Recent studies have identified at least three protein families as lipid translocases (Table 1): (1) a subfamily of P-type ATPases, also known as aminophospholipid translocases, which flip PS and PE specifically; (2) ATP-binding cassette (ABC) transporters that flop glycerophospholipids with little selectivity; and (3) lipid scramblases, which randomize the transbilayer distribution of all glycerophospholipid classes. In contrast to the asymmetry within the plasma membrane, the glycerophospholipid distribution between the two leaflets of the endoplasmic reticulum (ER) membrane is almost symmetrical. Although glycerophospholipids are synthesized in the cytosolic side of the ER, the ER membrane remains symmetrical due to rapid translocation of the lipids, which is independent of metabolic energy. This finding has led to the idea that a glycerophospholipid translocase exists in the ER. However, another interesting possibility was proposed from studies using model membranes. In those studies, liposomes containing only transmembrane peptides or proteins, and not a specific translocase, exhibited the flip-flop of fluorescent-labeled phospholipids (NBD-phospholipids). Moreover, incorporation of cholesterol into the liposome had an inhibitory effect on the peptide-induced flop. In natural, cholesterol is scarce in the ER membranes but abundant in the plasma membrane. Considering their observations, Kol et al. proposed that the flip-flop of glycerophospholipids within the cholesterol-low ER can be induced by the presence of a 1542 Vol. 29, No. 8