Aminophospholipid Flippases (P4-Adenosine Triphosphatase Family)/Translocases, Floppases, Scramblases, and Phospholipid Asymmetry

In most, if not all, cellular membranes phospholipids are distributed asymmetrically between the two leaflets, a property that is critical to membrane function. Thus, in addition to the flippases crucial to uniform expansion of the bilayer in the ER during membrane biogenesis, another set of flippases is required to maintain the proper distribution of phospholipids between the two leaflets of membranes in the various cellular compartments. The combined action of aminophospholipid flippases (P4-adenosine triphosphatase (ATPase) family members), two types of outwardly driven floppases (multidrug resistance, MDR, P-glycoprotein, other members of the MDR family, and members of the multidrug resistance-associated protein, MRP, subfamily) and possibly the adenosine triphosphate (ATP)-independent, Ca2+-activated, bidirectional scramblases (Figure 1(c)) are believed to play a role in the asymmetric distribution of PC and other membrane phospholipids between the two leaflets of the plasma membrane (PM) and other cellular membranes.

The best characterized of the candidate flippases is the ATP/Mg2+-dependent aminophospholipid flippase (P4-ATPase family). The properties of this type of flippase have been studied extensively, and progress has been made in purifying the protein component(s). It has been found in the PM of erythrocytes and other mammalian cells, synaptosomes, chromaffin granules, and secretory vesicles. This flippase appears to play a direct role in maintaining the enrichment of phosphatidylserine (PS) and phosphatidylethanolamine (PE) in the inner leaflet of the PM by moving the two aminophospholipids from the outer to the inner leaflet of the PM against a concentration gradient at the expense of ATP. In Figure 1(b) (left) the lipid moiety would be diacylglycerol and the polar headgroup ( ) would be either phosphorylserine or phosphorylethanolamine. The loss of this activity due to diminishing ATP pools or the loss of the protein(s) allows PE/PS to diffuse back to the outer monolayer where the surface alteration is recognized by the immune system as an early signal in apoptosis.

However, inhibition of the flippase or loss of ATP is insufficient to cause a rapid loss of PM PS asymmetry. Rapid PS externalization requires the additional activation of a (Ca2+-dependent) scramblase. The bidirectional, ATP-independent, Ca2+-activated scramblase (Figure 1(c)) plays an important role in platelet activation, blood clotting, and apoptosis.

There is good evidence that floppases mediate the ATP-dependent translocation of cholesterol, PC, and sphingolipids from the cytoplasmic to the external leaflet of the PM.