Membrane lipids distribution

Proteins that can flip phospholipids from one side of a bilayer to the other have also been identified in several tissues (Figure 9.11). Called flippases, these proteins reduce the half-time for phospholipid movement across a membrane from 10 days or more to a few minutes or less. Some of these systems may operate passively, with no required input of energy, but passive transport alone cannot establish or maintain asymmetric transverse lipid distributions. However, rapid phospholipid movement from one monolayer to the other occurs in an ATP-dependent manner in erythrocytes. Energy-dependent lipid flippase activity may be responsible for the creation and maintenance of transverse lipid asymmetries. 

Allan, D., Mapping the lipid distribution in the membranes of BHK cells, Molec. Membr. Biol. 13, 81-84 (1996). 

Figure 3 A hydrophobic permeant must negotiate through a complex series of diffu-sional and thermodynamic barriers as it penetrates into a cell. The lipid and protein compositions and charge distribution of the inner and outer leaflets of the membrane lipid bilayer can play limiting roles, particularly at the tight junction. Depending upon the permeant s characteristics, it may remain within the plasma membrane or enter the cytoplasm, possibly in association with cytosolic proteins, and partition into cytoplasmic membranes.

At a more molecular level, the influences of the composition of the membrane domains, which are characteristic of a polarized cell, on diffusion are not specifically defined. These compositional effects include the differential distribution of molecular charges in the membrane domains and between the leaflets of the membrane lipid bilayer (Fig. 3). The membrane domains often have physical differences in surface area, especially in the surface area that is accessible for participation in transport. For example, the surface area in some cells is increased by the presence of membrane folds such as microvilli (see Figs. 2 and 6). The membrane domains also have differences in metabolic selectivity and capacity as well as in active transport due to the asymmetrical distribution of receptors and transporters. 

Proulx [30] summarized the published lipid compositions of BBM isolated from epithelial cells from pig, rabbit, mouse and rat small intestines. Table 3.1 shows the lipid make-up for the rat, averaged from five reported studies [30], On a molar basis, cholesterol accounts for about 50% of the total lipid content (37% on a weight basis). Thus, the cholesterol content in BBM is higher than that found in kidney epithelial (MDCK) and brain endothelial cells (Table 3.1). Slightly different BBM lipid distribution was reported by Alcorn et al. [31] here, the outer (luminal) leaflet of the BBM was seen to be rich in sphingomyelin content, while the inner leaflet (cytosol) was rich in PE and PC. Apical (brush border) and basolateral lipids are different in epithelia. The basolateral membrane content (not reported by... 

In the following section, the role of the various types of complexes mentioned above will be discussed with regard to various mechanisms of interactions at biological interphases. It is clear that metal ions and hydrophilic complexes cannot distribute into the membrane lipid bilayer or cross it. The role of hydrophilic ligands has thus to be discussed in relation to binding of metals by biological ligands. In contrast, hydrophobic complexes may partition into the lipid bilayer of membranes (see below, Section 6). 

Membranes and models membrane organization (e.g. membrane domains, lipid distribution, peptide association, lipid order in vesicles, membrane fusion assays, etc.)... 

K. Gaus, M. Rodriguez, K. R. Ruberu, I. Gelissen, T. M. Sloane, L. Kritharides, and W. Jessup. Domain-specific lipid distribution in macrophage plasma membranes../. Lipid Res. 46 1526-1538 (2005). 

It can be seen from Figure 1 that the choline-containing phospholipids, phosphatidylcholine and sphingomyelin are localized predominantly in the outer monolayer of the plasma membrane. The aminophospholipids, conprising phosphatidylethanolamine and phosphatidylserine, by contrast, are enriched in the cytoplasmic leaflet of the membrane (Bretcher, 1972b Rothman and Lenard, 1977 Op den Kamp, 1979). The transmembrane distribution of the minor membrane lipid components has been determined by reaction with lipid-specific antibodies (Gascard et al, 1991) and lipid hydrolases (Biitikofer et al, 1990). Such studies have shown that phosphatidic acid, phosphatidylinositol and phosphatidylinositol-4,5-fc -phosphate all resemble phosphatidylethanolamine in that about 80% of the phospholipids are localized in the cytoplasmic leaflet of the membrane. 

An account of how membrane lipids are distributed throughout the cell and topologically across membranes has been given by van Meer (2000). The process is initiated during membrane biogenesis and is sustained and augmented by phospholipid translocases as membranes are sorted and differentiated throughout the cell. 

While examples such as these provide evidence that strong interactions of negatively-charged membrane lipids with membrane proteins the role in maintaining asymmetric distributions of lipids aaoss biological membranes is unclear. In any event such effects are likely to be of minor importance relative to actively mediated phospholipid translocation processes. 

Diacylglycerol, on the other hand, is lipid soluble and remains in the lipid bilayer of the membrane. There it can activate protein kinase C (PKC), a very important and widely distributed enzyme which serves many systems through phosphorylation, including neurotransmitters (acetylcholine, a,- and P-adrenoceptors, serotonin), peptide hormones (insulin, epidermal growth hormone, somatomedin), and various cellular functions (glycogen metabolism, muscle activity, structural proteins, etc.), and also interacts with guanylate cyclase. In addition to diacylglycerol, another normal membrane lipid, phos-phatidylserine, is needed for activation of PKC. The DG-IP3 limbs of the pathway usually proceed simultaneously. 

Chemical analyses of membranes isolated from various sources reveal certain common properties. Each kingdom, each species, each tissue or cell type, and the organelles of each cell type have a characteristic set of membrane lipids. Plasma membranes, for example, are enriched in cholesterol and contain no detectable cardiolipin (Fig. 11-2) in the inner mitochondrial membrane of the hepatocyte, this distribution is reversed very low cholesterol and high cardiolipin. Cardiolipin is essential to the function of certain proteins of the inner mitochondrial membrane. Cells clearly have mechanisms to control the kinds and amounts of membrane lipids they synthesize and to target specific lipids to particular organelles. In many cases, we can surmise the adaptive advantages of distinct combinations of membrane lipids in other cases, the functional significance of these combinations is as yet unknown. 

Plasma membrane lipids are asymmetrically distributed between the two monolayers of the bilayer, although the asymmetry, unlike that of membrane proteins, is not absolute. In the plasma membrane of the erythrocyte, for example, choline-containing lipids (phosphatidylcholine and sphingomyelin) are typically found in the outer (extracellular or exoplasmic) leaflet (Fig. 11-5), whereas phosphatidylserine, phosphatidyl-ethanolamine, and the phosphatidylinositols are much more common in the inner (cytoplasmic) leaflet. Changes in the distribution of lipids between plasma membrane leaflets have biological consequences. For example, only when the phosphatidylserine in the plasma membrane moves into the outer leaflet is a platelet able to play its role in formation of a blood clot. For many other cells types, phosphatidylserine exposure on the outer surface marks a cell for destruction by programmed cell death. 

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