Lipid Domains at the Plasma Membrane of Red Blood Cells: Organization and Involvement in Deformation

Abstract

Erythrocytes are highly deformable cells that go through capillaries eight times-narrower than their diameter to deliver oxygen throughout the body. This deformability is linked to erythrocytes specific features such as their biconcave shape, their highly regulated hemoglobin concentration and the strong anchorage of their membrane to the underlying cytoskeleton. Based on our recent evidence for submicrometric lipid domains upon labeling of cholesterol and polar lipids (sphingomyelin, phosphatidylcholine, ganglioside GM1) in erythrocyte outer plasma membrane leaflet, we here explore the mapping of lipid domains in erythrocytes at resting state and under deformation. Thanks to differential properties between cholesterol- and polar lipid-enriched domains (curvature association, lipid order, temperature dependence, cholesterol content dependence) and partial spatial dissociation, we suggest the coexistence of at least two types of lipid domains at the erythrocyte surface at resting state: those enriched in cholesterol and preferentially associated with high-curvature membranes and those mostly enriched in phosphatidylcholine and ganglioside GM1 and associated with low-curvature membranes. Biophysical properties of these domains are currently explored by atomic force microscopy and force correlation spectroscopy. Lipid domains abundance, composition and biophysical properties are differentially modulated by (i) impairment of erythrocyte deformability (energy depletion, modulation of anchorage to the cytoskeleton by pharmacological and genetic approaches), (ii) simulation of deformation (calcium channel activation, stretching in silicon chambers) and (iii) simulation of shape restoration after deformation (stimulation of calcium efflux). Indeed, high-curvature cholesterol-enriched domains gather under deformation while low-curvature domains become enriched in sphingomyelin and lose some of their ganglioside GM1 enrichment. We hypothesize that cholesterol-enriched domains can help to stabilize high curvature membranes during deformation while polar lipid-enriched domains, especially those enriched in sphingomyelin, are involved into calcium balance regulation during or after deformation. This hypothesis is under investigation.