The Journal of Experimental Biology 200, 2927–2936 (1997) 2927 Printed in Great Britain © The Company of Biologists Limited 1997 JEB1204 REVIEW CELL MEMBRANE LIPID COMPOSITION AND DISTRIBUTION: IMPLICATIONS FOR CELL FUNCTION AND LESSONS LEARNED FROM PHOTORECEPTORS AND PLATELETS KATHLEEN BOESZE-BATTAGLIA1,* AND RICHARD J. SCHIMMEL2 1Department of Molecular Biology and 2Department of Cell Biology, University of Medicine and Dentistry of New Jersey, School of Osteopathic Medicine, Stratford, NJ 08084, USA Accepted 17 September 1997 Summary Photoreceptor rod cells and blood platelets are providing a thermodynamically unfavorable environment remarkably different, yet both illustrate a similar for the sterol. Cholesterol enrichment of platelets renders phenomenon. Both are strongly affected by membrane these cells more responsive to stimuli of aggregation. cholesterol, and the distribution of cholesterol in the Stimuli for platelet aggregation cause a rapid transbilayer membranes of both cell types is determined by the lipid movement of cholesterol from the outer monolayer. This composition within the membranes. In rod cells, stimulus-dependent redistribution of cholesterol appears cholesterol strongly inhibits rhodopsin activity. The to result from the concomitant movement of relatively higher level of cholesterol in the plasma phosphatidylethanolamine into the outer monolayer. The membrane serves to inhibit, and thereby conserve, the attractive, yet still unproven, hypothesis is that activity of rhodopsin, which becomes fully active in the cholesterol translocation plays an important role in the low-cholesterol environment of the disk membranes of overall platelet response and is intimately related to the these same cells. This physiologically important sensitizing actions of cholesterol on these cells. partitioning of cholesterol between disk membranes and plasma membranes occurs because the disk membranes Key words: lipid, cell membrane, photoreceptor, rod cell, are enriched with phosphatidylethanolamine, thus phosphatidylethanolamine, platelet, cholesterol. Introduction With remarkable foresight, Davson and Danielli (1952) transmembrane proteins have a degree of motion which, in clearly articulated the importance of cell membranes: ‘It can turn, can have a dramatic impact upon protein activity. The truely be said of living cells, that by their membranes ye shall characteristics of the lipid matrix depend upon the physical know them’. Cell membranes were known then to be properties of the individual lipid components in the membrane. composed of lipids and proteins: lipids making membranes Membrane protein activity is influenced by the surrounding nearly impermeable to most water-soluble solutes; proteins lipid matrix and specifically by the association between lipids serving as transporters and signaling devices. The classic and proteins at the lipid–protein interface. At any instant, a deductions of Gorter and Grendel (1925) became the dogma population of lipids is always associated with a membrane that membrane lipids are arranged in a bilayer configuration: protein. Depending on the time these lipids spend associated parallel sheets of phospholipids with polar or charged head with the protein, they are classified as either restricted or groups oriented towards the aqueous environment and acyl interfacial lipids. Lipids that have a long residence time on the chains interacting within the hydrophobic membrane core. The protein and exchange with lipids in the surrounding membrane acceptance of the idea that cell membranes were not merely at a slow rate are termed motionally restricted. The nature of static barriers containing immobile proteins but dynamic the association between this group of lipids and proteins and lipid–protein matrices contributing to the regulation of cell the type of lipid that has access to the protein in this restricted function can be attributed to publication of the fluid mosaic domain modulates the activity of the protein. Several examples model of cell membranes (Singer and Nicolson, 1972). This of membrane proteins that are influenced by specific restricted model viewed membrane lipids as a viscous matrix in which lipids are presented in Table 1. In some of these cases, protein *Author for correspondence and present address: Department of Molecular Biology, 2 Medical Center Drive, UMDNJ School of Osteopathic Medicine, Stratford, NJ 08084, USA (e-mail: [email protected]). 2928 K. BOESZE-BATTAGLIA AND R. J. SCHIMMEL Table 1. Examples of membrane proteins that are influenced by specific restricted lipids Membrane protein Regulatory lipid Effect References Mitochondrial ADP Cardiolipin Necessary for nucleotide exchange Beyer and Klingenberg (1985) exchange Na+/K+-ATPase Cholesterol Necessary for activity Yeagle et al. (1988) Esmann and Marsh (1985) Anion transport (Band 3) Cholesterol Necessary for activity Klappauf and Schubert (1977) Schubert and Boss (1982) Ca2+-ATPase in muscle Phosphatidylethanolamine Necessary for activity Cheng et al. (1986) sarcoplasmic reticulum Hildago et al. (1982) Glycophorin Phosphatidylinositol Necessary for activity Yeagle and Kelsey (1989) Glycophorin Phosphatidylinositol phosphates Promotes binding to cytoskeleton Anderson and Marchesi (1985) Anderson and Lovrien (1984) β-Hydroxybutyrate Phosphatidylcholine Necessary for activity Isaacson et al. (1979) dehydrogenase activity is subject to additional modulation by a second class containing lipids, phosphatidylcholine and sphingomyelin, are of lipids, the interfacial lipids. found preferentially in the outer monolayer and amine- Membrane proteins may also have associated with them a containing lipids, phosphatidylethanolamine and sufficient number of specific or non-specific lipids which form phosphatidylserine, are localized to the inner monolayer. The a coat or annulus around the circumference of the protein. Such establishment and maintenance of phospholipid asymmetry interfacial lipids exchange rapidly with the surrounding lipids occurs through a specific ATP-dependent transport protein, the and determine the bulk properties of the lipid matrix. aminophospholipid translocase (for a review, see Devaux, Phosphatidylserine and stearic acid show a high affinity for 1991), which translocates phosphatidylethanolamine and contact with the transmembrane portion of the Na+/K+- phosphatidylserine between the monolayers. ATPase, while rhodopsin requires an unsaturated fatty-acid- After phospholipids, cholesterol is the next most abundant rich phospholipid annulus for function (Watts et al. 1979). It constitutive lipid. The planar sterol ring and the hydrophobic is important to point out that, in other regions of the membrane, tail orient cholesterol within the membrane core, while the 3- lipid–lipid or protein–protein interactions predominate and β-hydroxyl group allows cholesterol to contribute to the modulate protein function by changing the properties of the surface properties of the bilayer. The structure of cholesterol lipid–protein interface. allows it to reduce the freedom of movement of phospholipid Phosphatidylcholine, phosphatidylethanolamine, acyl chains, thus rigidifying the membrane, which can have a phosphatidylserine and phosphatidylinositol are the dramatic impact upon membrane function. This phenomenon constitutive lipids that provide a structural framework and the is referred to as a ‘condensing effect’ (Demel et al. 1972). The environment that defines the functional parameters associated importance of the contribution of cholesterol to membrane with individual cell types. Phosphatidylcholine, properties is reflected in its ubiquitous distribution and its phosphatidylserine and phosphatidylinositol provide for necessity for normal cell growth and function. However, high hydrated or charged membrane surfaces, allowing water and/or levels of membrane cholesterol, often secondary to high levels ions to bind to their polar headgroups. In contrast, surfaces rich of serum cholesterol, exert deleterious effects on cells. in phosphatidylethanolamine are hydrophobic, poorly hydrated Like phospholipids, cholesterol is also distributed non- and promote surface-to-surface interactions without direct uniformly in cell membranes (Dawidowicz, 1987; Boesze- protein binding. Because phosphatidylethanolamine is not Battaglia et al. 1996; Lange, 1992). An extreme example of readily hydrated, it promotes the formation of non-bilayer non-uniform cholesterol distribution is in platelet membranes structures (i.e. hexagonal II phase) to compensate for the which, it is suggested, contain regions devoid of cholesterol hydrophobic effect. The inherent instability of this (i.e. ‘cholesterol-free patches’) (Gordon et al. 1983). Sterol phospholipid is necessary in such cellular functions as carrier proteins have been identified that deliver sterol to the membrane fusion. plasma membrane from the endoplasmic reticulum (for a Cell membranes also contain trace amounts of transient review, see Schroeder et al. 1996), but there is no compelling lipids, which exist in the membrane for only brief periods, evidence for a role of these proteins in transmembrane serving predominantly as second messengers (for a review, see cholesterol distribution; similarly, an intramembrane Ghosh et al. 1997). Phospholipids are asymmetrically cholesterol-specific translocase has not been identified. distributed between the inner and outer monolayer of cell With the acceptance of the fluid mosaic model, the concept membranes (for a review, see Op den Kamp, 1979); choline- of