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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.

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Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.

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Phospholipid Bilayers

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Cells are separated from their environment by lipid bilayers

The fundamental importance of lipids in membrane structure was established early in this century by demonstrations that positive correlations exist between cell membrane permeabilities to small nonelectrolytes and the oil/water partition coefficients of these molecules. Contemporary measurements of the electrical impedance of cell suspensions suggested that cells are surrounded by a hydrocarbon barrier, which was first estimated to be about 3.3 nm thick. It was originally thought that a membrane containing a lipid monolayer could account for these data. However, subsequent experiments established that the ratio of the area of a monolayer formed from erythrocyte membrane lipids to the surface area of these cells is nearly 2. These and other studies of the physical chemistry of lipids fortified the concept that a continuous lipid bilayer is a major component of cell membranes. This concept has received support from many other studies, including the interpretation of X-ray diffraction data obtained from intact cell membranes.

Forces acting between lipids and between lipids and proteins are primarily noncovalent, consisting of electrostatic, hydrogen-bonding and van der Waals' interactions. Although these are weak interactions relative to covalent bonds, their sum can produce very stable associations. Ionic and polar parts of molecules exposed to water will become hydrated. Substances dissolve in a solvent only if their molecules interact with the solvent more strongly than with each other. Complex molecules may have two or more surface domains that differ in polarity. In aqueous solution their apolar surfaces form an internal hydrophobic phase that minimizes their exposure to water and their more polar surfaces form an external hydrated phase. Molecules with segregated polar and nonpolar surfaces are termed amphipathic. These include most biological lipids and many proteins.

Amphipathic molecules form bilayered lamellar structures spontaneously if they have an appropriate geometry

Most of the major cell membrane lipids have a polar head, commonly a glycerophosphorylester moiety and a hydrocarbon tail, usually consisting of two esterified fatty acids (Chap. 3). The head groups can interact with water and aqueous phase solutes, whereas the nonpolar tails aggregate to form an internal phase.

Three principal phases with different structures are formed by phospholipids in the presence of water [1] (Fig. 2-2). Although the lamellar, or bilayer, structure is generally found in cell membranes, the two hexagonal phases probably occur during some membrane transformations. The importance of molecular geometry for bilayer stability is illustrated by the effects of the phospholipase A2 component of many venoms: they remove one fatty acid from a phospholipid to produce lysophosphatides, which ultimately destabilize bilayers relative to hexagonal phase structures. In sufficient amounts, lysophosphatides disrupt cell membranes and lyse cells. Detergents are amphipathic molecules with similar abilities to transform lipid bilayers into water-soluble micelles. In contrast to the destabilizing effects of lysophosphatides and other detergents, cholesterol stabilizes bilayers by intercalating at the interface between head and tail regions of phospholipid so as to satisfy the bulk requirements for a planar geometry.

Figure 2-2. Complex lipids interact with water and with each other to form different states of aggregation, or “phases,” shown here schematically.

Figure 2-2

Complex lipids interact with water and with each other to form different states of aggregation, or “phases,” shown here schematically. Open circles or ellipses represent the more polar head groups, and dark lines and areas represent nonpolar hydrocarbon (more...)

Multilamellar bilayer structures (Fig. 2-2) form spontaneously if small amounts of water are added to solid or liquid phase phospholipids. These can be dispersed in water to form vesicular structures called liposomes. These are often employed in studies of bilayer properties and may be combined with membrane proteins to reconstitute functional membrane systems. A valuable technique for studying the properties of proteins inserted into bilayers employs a single bilayer lamella, also termed a black lipid membrane, formed across a small aperture in a thin partition between two aqueous compartments. Because pristine lipid bilayers have very low ion conductivities, the modifications of ion-conducting properties produced by membrane proteins can be measured with great sensitivity (Chap. 6).

In aqueous systems, phospholipid structures may manifest either gel, that is, rigid, or liquid-crystalline, that is, two-dimensionally fluid, properties. In the case of pure phospholipids, these states interconvert at a well-defined transition temperature, Tc, that increases with alkyl chain length and decreases with introduction of unsaturation. In cell membranes, there is marked heterogeneity in both the polar and nonpolar domains of the bilayer. Alkyl chain heterogeneity and the presence of cholesterol maintain cell membrane bilayers in the fluid state over a broad temperature range. Bilayer fluidity causes membrane lipids and proteins to diffuse rapidly within the plane of the bilayer.

Functional importance of bilayer asymmetry. Although there is rapid diffusion within the plane of a bilayer, spontaneous transverse migration of phospholipids from one bilayer leaflet to another is rare. This allows the two leaflets of a cell membrane bilayer to have very different compositions (Chap. 3). Aminophospholipids are normally confined almost exclusively to the cytoplasmic leaflet, whereas most glycolipids and sphingolipids are in the extracytoplasmic leaflet. This is accomplished by an ATP-dependent process that “pumps” the head groups of aminophospholipids toward the cytoplasmic surface. A second ATP-dependent pumping process may be involved in maintaining the extracytoplasmic orientation of phosphatidylcholine (Chap. 5). High intracellular Ca2+, which can arise from any condition that depletes intracellular ATP, activates a “scramblase” protein, which catalyses random transverse lipid movements. The appearance of substantial amounts of phosphatidylserine on outer cell surfaces can initiate apoptosis and phagocytosis [2].

Insertion of lipids into bilayers. Most biosynthesis of membrane lipids occurs in the endoplasmic reticulum (ER) (Chap. 3). Glycosphingolipids can segregate laterally in the bilayer to form microdomains, or “rafts,” with cholesterol [3]. In apical membranes of epithelial cells, these domains are associated with the sites of formation of small vesicles, called “caveolae” (see below), which transport cholesterol and, perhaps, other lipids to plasma membranes [4].

Most bilayer phospholipids are physically constrained by association with integral membrane proteins

In addition to interacting with each other to form the bilayer, membrane lipids may interact to varying degrees with membrane proteins [5]. Some physical measurements, such as electron spin resonance, have indicated that the acyl moieties of lipids immediately surrounding integral membrane proteins are motionally restricted and reoriented relative to the bilayer. This “annulus” fraction can comprise 20 to 90% of the total membrane phospholipid. Because the annulus lipids appear to equilibrate rapidly, within microseconds, with the bulk membrane lipids in comparison with the time scale of most enzyme-catalyzed reactions, which occur in milliseconds, the significance of such interactions has been questioned. However, phosphatidylethanol-amine is now known to be a component of the crystalline structure of the membrane protein, cytochrome oxidase [6]. Some proteins, including certain integral membrane proteins, contain domains that can interact directly and strongly with phospholipids (see below).

Diffusional flow of water directly through lipid bilayers largely accounts for the water permeability of most cell membranes

The water permeability of ion channels is estimated to account for only about 1% of the total cell water permeability. Measurements of water permeability of bilayers of varying lipid composition have ranged from 2 to 1,000 × 10−5 cm2/sec [7]. Measurements of cell membrane water permeabilities are in the same range for many cell types. Erythrocytes are a known exception, with a water permeability of about 2 × 10−2 cm2. The high water permeability of the plasma membranes of erythrocytes, kidney epithelia, certain glia and other cells results from the presence of specific membrane proteins, designated aquaporins. These are the eukaryotic members of a large and widespread family of membrane channel proteins that select water and, in some cases, admit small neutral molecules such as urea and glycerol [8]. Aquaporin-2 mediates vasopressin-sensitive water transport [9]. Aquaporin-4 is expressed in high levels in certain glial and ependymal cells [10].

The head-group regions of phospholipid monolayers facilitate lateral diffusion of protons and possibly of other ions

In model systems, pH changes have been shown to be transmitted more rapidly along these interfaces than in bulk solution. This may have particular importance in mitochondrial ATP synthesis and other processes that depend on transmembrane proton gradients [11]. This high mobility may not be restricted to protons: nuclear magnetic resonance studies have shown that the exchange of metal cations among phospholipid head groups can also be more rapid than in free solution.

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Copyright © 1999, American Society for Neurochemistry.
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