Modelling of phospholipid translocation in the erythrocyte membrane: a combined kinetic and thermodynamic approach

A mathematical model for the dynamics of transbilayer movements of lipids in the erythrocyte plasma membrane is presented. It takes into account an active carrier which mediates the ATP-dependent translocation of phosphatidylserine and phosphatidylethanolamine from the outer to the cytoplasmic leaflet of the membrane and passive fluxes of these lipids as well as of phosphatidylcholine, sphingomyelin and cholesterol between both layers. It is assumed that the passive fluxes are driven by concentration gradients of the lipids and by mechanical forces which result from area limitation for lipid occupation in both leaflets. Compared with a previous mathematical treatment of lipid translocation processes in the erythrocyte membrane the present model is much closer to realistic conditions, e.g. concerning the number of lipid species involved. Furthermore, the use of linear flux-force relationships as known from irreversible thermodynamics allows a simpler treatment of the passive fluxes than before and provides a relevant framework to study the coupling between the various processes. The model allows to simulate the time dependent changes of lipid concentrations which take place after activation or inhibition of ATP-dependent translocation. Using realistic parameter values it explains in quantitative terms the stationary asymmetric distribution of lipids under in vivo conditions. Using principles of metabolic control analysis we are able to quantify the role of the various active and passive processes in determining the asymmetric distribution for each lipid species.