The Structure of the Plasma Membrane

Before we consider the mechanisms that allow cells to maintain the differences in ECF and ICF shown in Table 2-1, it will be helpful to look at the structure of the outer membrane of the cell, the plasma membrane. The control mechanisms responsible for the differences between ICF and ECF reside within the plasma membrane, which forms the barrier between the intracellular and extracellular compartments.

It has long been known that the contents of a cell will leak out if the cell is damaged by being poked or prodded with a glass probe. Also, some dyes will not enter cells when dissolved in the ECF, and the same dyes will not leak out when injected inside cells. These observations, first made in the nineteenth century, led to the idea that there is a selectively permeable barrier the plasma membrane separating the intracellular and extracellular fluids.

The first systematic observations of the kinds of molecules that would enter cells and the kinds that were excluded were made by Overton in the early part of the twentieth century. He found that, in general, substances that are highly soluble in lipids enter cells more easily than substances that are less soluble in lipids. Lipids are molecules that are not soluble in water or other polar solvents, but are soluble in oil or other nonpolar solvents. Thus, Overton suggested that the plasma membrane of a cell is made of lipids and that substances can cross the membrane if they can dissolve in the membrane lipids.

There were some exceptions to the general lipid solubility rule. Electrically charged substances, like potassium and chloride ions, are almost totally insoluble in lipids, yet they manage to cross the plasma membrane. Other substances, such as urea, entered cells more easily than expected from their lipid solubility alone. To take account of these exceptions, Overton suggested that the lipid membrane is shot through with tiny holes or pores that allow highly water soluble (hydrophilic) substances, such as ions, to cross the membrane. Only hydrophilic substances that are small enough to fit through these small aqueous pores can cross the membrane. Larger molecules like proteins and amino acids cannot fit through the pores and thus cannot cross the membrane without the help of special transport mechanisms.

The molecules of the lipid skin of cell membranes appear to be arranged in a layer only two molecules thick. Evidence for this arrangement was obtained from experiments in which the lipids were chemically extracted from the plasma membranes of cells and spread out on a trough of water in such a way that they formed a film only one molecule thick. When the area of this monolayer "oil slick" was measured, it was found to be about twice the total surface area of the intact cells from which the lipids were obtained. This suggests that the membrane of the intact cells was two molecules thick. Such a membrane is called a lipid bilayer membrane.

The bilayer arrangement of the cell membrane makes chemical sense when we consider the characteristics of the particular lipid molecules found in the plasma membrane. The cell lipids are largely phospholipids, which are molecules that have both a polar region that is hydrophilic and a nonpolar region that is hydrophobic. When surrounded by water, these lipid molecules tend to aggregate, with the hydrophilic regions oriented outward toward the surrounding water and the hydrophobic regions pointed inward toward each other. When spread out in a sheet with water on each side of the sheet, the phospholipids can maintain their preferred state by forming a bimolecular sandwich, with the hydrophilic parts on the outside toward the water, and the hydrophobic parts in the middle, pointed toward each other. This bilayer model for the cell plasma membrane is illustrated in Figure 2-1.

Figure 2-1 also shows another important characteristic of cell membranes. They contain not only lipid molecules but also protein molecules. Some proteins are attached to the inner or outer surface of the cell membrane, and others penetrate all the way through the membrane so that they form a bridge from one side to the other. Some of these transmembrane proteins form the aqueous pores, or channels, that allow ions and other small hydrophilic molecules to cross the membrane. If we separate membranes from the rest of the cell and

Proteins

Proteins

pore

Figure 2-1 A schematic diagram of a section of the plasma membrane. The backbone of the membrane is a sheet of lipid molecules two molecules thick. Inserted into this sheet are various types of protein molecules. Some protein molecules extend all the way across the sheet, from the inner to the outer face. These transmembrane proteins sometimes form aqueous pores or channels through which small hydrophilic molecules, such as ions, can cross the membrane. The diagram shows two such channels; one is cut in cross-section to reveal the interior of the pore.

pore

Figure 2-1 A schematic diagram of a section of the plasma membrane. The backbone of the membrane is a sheet of lipid molecules two molecules thick. Inserted into this sheet are various types of protein molecules. Some protein molecules extend all the way across the sheet, from the inner to the outer face. These transmembrane proteins sometimes form aqueous pores or channels through which small hydrophilic molecules, such as ions, can cross the membrane. The diagram shows two such channels; one is cut in cross-section to reveal the interior of the pore.

analyze their composition, we find that, by weight, only about one-third of the membrane material is lipid; most of the rest is protein. Thus, the lipids form the backbone of the membrane, but proteins are an important part of the picture. We will see later that the proteins are very important in controlling the movement of substances, particularly ions, across the cell membrane.

We can get an idea of the importance of membrane proteins for life by examining how much of the entire genome of a simple organism is taken up by genes encoding membrane proteins. One of the smallest genomes of any free-living organism is that of Mycoplasma genitalium, a microbe whose genome can be regarded as close to the minimum required for an independent, cellular life form. The DNA of M. genitalium has been completely sequenced, revealing a total of 482 individual genes. Of this total, 140 genes, or about 30%, code for membrane proteins. Thus, M. genitalium expends a large fraction of its total available DNA for the membrane proteins that sit at the interface between the microbe and its external environment. This points out the central role of these proteins in the maintenance of cellular life.

Anatomical evidence also supports the model shown in Figure 2-1. The cell membrane is much too thin to be seen with the light microscope. In fact, it is almost too thin to be seen with the electron microscope. However, with an electron microscope it is possible to see at the outer boundary of a cell a three-layered (trilaminar) profile like a railroad track, with a light central region separating two darker bands. Figure 2-2 is an example of an electron micrograph

Figure 2-2 High-power electron micrograph of the plasma membranes of two neighboring cells. Note the two dark bands separated by a light region at the outer surface of each cell. The two cells are nerve cells from the brain, and the point of close contact between them is a synapse, the point of information transfer in the nervous system. Note also the membrane-bound intracellular structures (labeled SV), called synaptic vesicles, inside one of the cells; the vesicle membranes also have the trilaminar profile seen in the plasma membranes. We will learn more about synaptic vesicles and synapses in Chapters 8 and 9. (Courtesy of A. L. deBlas of the University of Connecticut.)

showing the plasma membranes of two cells lying in close contact. The interpretation of the trilaminar profile is that the two dark bands represent the polar heads of the membrane phospholipids and protein molecules on the inner and outer surfaces of the membrane and that the lighter region between the two dark bands represents the nonpolar tails of the lipid molecules. The total thickness of the sandwich is about 7.5 nm. The lighter-colored "fuzz" surrounding the trilaminar profiles of the two cell membranes in Figure 2-2 consists in part of portions of membrane-associated protein molecules extending out into the intracellular and extracellular spaces. The two cells shown in Figure 2-2 are nerve cells (neurons) in the brain, and the region of close contact is a specialized junction, called a synapse, where electrical activity is relayed from one nerve cell to another. The synapse is the basic mechanism of information transfer in the brain, and one of our major goals in this book is to understand how synapses work.

By using a special form of microscopy called freeze-fracture electron microscopy, it is possible to visualize more clearly the protein molecules that are embedded in the plasma membrane. A schematic representation of the freeze-fracture technique is shown in Figure 2-3. A small sample of the tissue to be examined is frozen in liquid nitrogen, and then a thin sliver of the frozen tissue is shaved off with a sharp knife. Because the tissue is frozen, however, the sliver is not so much sliced off as broken off from the sample. In some cases, like that shown in Figure 2-3, the line of fracture runs between the two lipid layers of the membrane bilayer, leaving holes where protein molecules are ripped out of the lipid monolayer and protrusions where membrane

Figure 2-3 Schematic illustration of the freeze-fracture procedure for electron microscopy. When a fracture line runs between the two lipid layers of the plasma membrane, some membrane proteins stay with one monolayer, others with the other layer. When the fractured surface is then examined with the electron microscope, the remaining proteins appear as protruding bumps in the surface.

Figure 2-3 Schematic illustration of the freeze-fracture procedure for electron microscopy. When a fracture line runs between the two lipid layers of the plasma membrane, some membrane proteins stay with one monolayer, others with the other layer. When the fractured surface is then examined with the electron microscope, the remaining proteins appear as protruding bumps in the surface.

proteins are ripped out of the opposing monolayer and come along with the shaved sliver. An example of such a freeze-fracture sample viewed through the electron microscope is shown in Figure 2-4. The membrane proteins appear as small bumps in the otherwise smooth surface of the plasma membrane, like grains of sand sprinkled on a freshly painted surface. In the discussion of the transmission of signals at synapses in Chapter 8, we will see other examples of freeze-fracture electron micrographs and see how they can provide important evidence about the physiological functioning of cells.

Figure 2-4 Example of a fractured membrane surface containing protein molecules, viewed through the electron microscope. The membrane surface shown is that of the presynaptic nerve terminal at the nerve-muscle junction, which will be discussed in detail in Chapter 8. The protein molecules are the small bumps scattered about on the planar surface of the membrane. (Reproduced from C.-P. Ko, Regeneration of the active zone at the frog neuromuscular junction. Journal of Cell Biology 1384;38:1685-1635; by copyright permission of the Rockefeller University Press.)

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