Nonequilibrium asymmetry in the living cell membrane

We will discuss how sustained nonequilibrium processes operating at the plasma membrane (PM) determine the dynamical organisation (both lateral and transverse) of lipids, their maintenance and control, under physiological conditions. These nonequilibrium processes include active contractile stresses arising from the inevitable interaction of the inner leaflet of the PM with the adjoining actomyosin cortex, and active flipping of specific lipids. Recently, we showed that the inner leaflet phosphatidylserine (PS) interacts with the actomyosin cortex and engages in a strong transbilayer coupling across the leaflets. Here we develop an active Flory-Huggins theory for the mesoscale segregation of liquid-ordered (lo)-liquid-disordered (ld) domains in an asymmetric membrane bilayer, that incorporates both active contractile stresses at the inner leaflet and transbilayer coupling across the leaflets. The interplay between chemical potential gradients, transbilayer coupling and active stresses drives a rich pattern of mesoscale lo domains - static, strongly fluctuating and moving active emulsions - even at temperatures beyond the equilibrium phase transition temperature. We study conditions under which domain registry and slippage could be observed. We end with a discussion on the role of active flippases on PS in maintaining the active mesoscale organisation.