Regulatory Mechanisms in Maintenance and Modulation of Transmembrane Lipid Asymmetry: Pathophysiological Implications

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Abstract
The two leaflets of the plasma membrane of eukaryotic cells differ in lipid composition: the outer leaflet comprises mainly neutral choline containing phospholipids, whereas the aminophospholipids reside almost exclusively in the cytoplasmic leaflet. The importance of transmembrane lipid asymmetry may be judged from the fact that the cell invests energy to maintain this situation for which at least two regulatory mechanisms are held responsible. A translocase, selective for aminophospholipids, acts as an ATP-dependent pump for rapid inward movement of phosphatidylserine (PS) and phosphatidylethanolamine; in addition, a non-selective, but also ATP-dependent pump causes outward movement of phospholipids, be it at a much lower rate compared to the inward transport by the aminophospholipid translocase. These two systems, acting in concert, are thought to be the main players in the maintenance of a dynamic equilibrium of the phospholipids over both membrane leaflets. Dissipation of membrane lipid asymmetry can be elicited in different cell types under a variety of conditions; in particular, platelets upon activation rapidly lose their normal plasma membrane lipid distribution, but also in other blood cells, lipid asymmetry can be lost, be it at a much lower rate and extent than in platelets. A putative protein, referred to as ‘scramblase’ has been described, which requires the continuous presence of elevated intracellular Ca2+-levels, to allow a rapid, nonselective and bidirectional transbilayer movement of phospholipids. Although scrambling of lipids does not require ATP as such, preliminary studies suggest the possible involvement of one or more phosphorylated proteins. The most prominent consequence of the loss of phospholipid asymmetry is exposure of PS in the outer leaflet of the plasma membrane. Surface-exposed PS serves several important physiological functions: it promotes assembly of enzyme complexes of the coagulation cascade, it forms a signal for cell-cell recognition, which is important for cell scavenging processes. Surface-exposure of PS is an early phenomenon of apoptosis and appears to be involved in efficient removal of these cells. In addition, PS in the outer leaflet of cells is thought to play a role in cell fusion processes. It may be clear from the foregoing, that the amount of PS present at the cell surface needs to be tightly controlled, and that an impairment of this process leads to either excessive- or diminished exposition of PS which may have several pathophysiological consequences.