The Cell and Its Functions

Water.

The principal fluid medium of the cell is water, which is present in most cells, except for fat cells, in a concentration of 70 to 85 percent. Many cellular chemicals are dissolved in the water. Others are suspended in the water as solid particulates. Chemical reactions take place among the dissolved chemicals or at the surfaces of the suspended particles or membranes.

Ions.

Important ions in the cell include potassium, magnesium, phosphate, sulfate, bicarbonate, and smaller quantities of sodium, chloride, and calcium. These ions are all discussed in more detail in Chapter 4, which considers the interrelations between the intracellular and extracellular fluids.

The ions provide inorganic chemicals for cellular reactions and also are necessary for operation of some of the cellular control mechanisms. For instance, ions acting at the cell membrane are required for transmission of electrochemical impulses in nerve and muscle fibers.

Proteins.

After water, the most abundant substances in most cells are proteins, which normally constitute 10 to 20 percent of the cell mass. These proteins can be divided into two types: structural proteins and functional proteins.

Structural proteins are present in the cell mainly in the form of long filaments that are polymers of many individual protein molecules. A prominent use of such intracellular filaments is to form microtubules that provide the “cytoskeletons” of such cellular organelles as cilia, nerve axons, the mitotic spindles of cells undergoing mitosis, and a tangled mass of thin filamentous tubules that hold the parts of the cytoplasm and nucleoplasm together in their respective compartments. Fibrillar proteins are found outside the cell, especially in the collagen and elastin fibers of connective tissue and in blood vessel walls, tendons, ligaments, and so forth.

The functional proteins are an entirely different type of protein and are usually composed of combinations of a few molecules in tubular-globular form. These proteins are mainly the enzymes of the cell and, in contrast to the fibrillar proteins, are often mobile in the cell fluid. Also, many of them are adherent to membranous structures inside the cell. The enzymes come into direct contact with other substances in the cell fluid and catalyze specific intracellular chemical reactions. For instance, the chemical reactions that split glucose into its component parts and then combine these with oxygen to form carbon dioxide and water while simultaneously providing energy for cellular function are all catalyzed by a series of protein enzymes.

Lipids.

Lipids are several types of substances that are grouped together because of their common property of being soluble in fat solvents. Especially important lipids are phospholipids and cholesterol, which together constitute only about 2 percent of the total cell mass. The significance of phospholipids and cholesterol is that they are mainly insoluble in water and therefore are used to form the cell membrane and intracellular membrane barriers that separate the different cell compartments.

In addition to phospholipids and cholesterol, some cells contain large quantities of triglycerides, also called neutral fat. In the fat cells, triglycerides often account for as much as 95 percent of the cell mass. The fat stored in these cells represents the body's main storehouse of energy-giving nutrients that can later be used to provide energy wherever in the body it is needed.

Carbohydrates.

Carbohydrates have little structural function in the cell except as parts of glycoprotein molecules, but they play a major role in nutrition of the cell. Most human cells do not maintain large stores of carbohydrates; the amount usually averages about 1 percent of their total mass but increases to as much as 3 percent in muscle cells and, occasionally, 6 percent in liver cells. However, carbohydrate in the form of dissolved glucose is always present in the surrounding extracellular fluid so that it is readily available to the cell. Also, a small amount of carbohydrate is stored in the cells in the form of glycogen, which is an insoluble polymer of glucose that can be depolymerized and used rapidly to supply the cells' energy needs.

The Cell Membrane Lipid Barrier Impedes Penetra­tion by Water-Soluble Substances.

Figure 2-3 shows the structure of the cell membrane. Its basic structure is a lipid bilayer, which is a thin, double-layered film of lipids—each layer only one molecule thick—that is continuous over the entire cell surface. Interspersed in this lipid film are large globular proteins.

The basic lipid bilayer is composed of three main types of lipids: phospholipids, sphingolipids, and cholesterol. Phospholipids are the most abundant of the cell membrane lipids. One end of each phospholipid molecule is soluble in water; that is, it is hydrophilic. The other end is soluble only in fats; that is, it is hydrophobic. The phosphate end of the phospholipid is hydrophilic, and the fatty acid portion is hydrophobic.

Because the hydrophobic portions of the phospholipid molecules are repelled by water but are mutually attracted to one another, they have a natural tendency to attach to one another in the middle of the membrane, as shown in Figure 2-3. The hydrophilic phosphate portions then constitute the two surfaces of the complete cell membrane, in contact with intracellular water on the inside of the membrane and extracellular water on the outside surface.

The lipid layer in the middle of the membrane is impermeable to the usual water-soluble substances, such as ions, glucose, and urea. Conversely, fat-soluble substances, such as oxygen, carbon dioxide, and alcohol, can penetrate this portion of the membrane with ease.

Sphingolipids, derived from the amino alcohol sphingosine, also have hydrophobic and hydrophilic groups and are present in small amounts in the cell membranes, especially nerve cells. Complex sphingolipids in cell membranes are thought to serve several functions, including protection from harmful environmental factors, signal transmission, and as adhesion sites for extracellular proteins.

The cholesterol molecules in the membrane are also lipids because their steroid nuclei are highly fat soluble. These molecules, in a sense, are dissolved in the bilayer of the membrane. They mainly help determine the degree of permeability (or impermeability) of the bilayer to water-soluble constituents of body fluids. Cholesterol controls much of the fluidity of the membrane as well.

Integral and Peripheral Cell Membrane Proteins.

Figure 2-3 also shows globular masses floating in the lipid bilayer. These membrane proteins are mainly glycoproteins. There are two types of cell membrane proteins: integral proteins that protrude all the way through the membrane and peripheral proteins that are attached only to one surface of the membrane and do not penetrate all the way through.

Many of the integral proteins provide structural channels (or pores) through which water molecules and water-soluble substances, especially ions, can diffuse between the extracellular and intracellular fluids. These protein channels also have selective properties that allow preferential diffusion of some substances over others.

Other integral proteins act as carrier proteins for transporting substances that otherwise could not penetrate the lipid bilayer. Sometimes these carrier proteins even transport substances in the direction opposite to their electrochemical gradients for diffusion, which is called “active transport.” Still others act as enzymes.

Integral membrane proteins can also serve as recep­tors for water-soluble chemicals, such as peptide hormones, that do not easily penetrate the cell membrane. Interaction of cell membrane receptors with specific ligands that bind to the receptor causes conformational changes in the receptor protein. This process, in turn, enzymatically activates the intracellular part of the protein or induces interactions between the receptor and proteins in the cytoplasm that act as second messengers, relaying the signal from the extracellular part of the receptor to the interior of the cell. In this way, integral proteins spanning the cell membrane provide a means of con­veying information about the environment to the cell interior.

Peripheral protein molecules are often attached to the integral proteins. These peripheral proteins function almost entirely as enzymes or as controllers of transport of substances through the cell membrane “pores.”

Membrane Carbohydrates—The Cell “Glycocalyx.”

Membrane carbohydrates occur almost invariably in combination with proteins or lipids in the form of glycoproteins or glycolipids. In fact, most of the integral proteins are glycoproteins, and about one tenth of the membrane lipid molecules are glycolipids. The “glyco” portions of these molecules almost invariably protrude to the outside of the cell, dangling outward from the cell surface. Many other carbohydrate compounds, called proteoglycans—which are mainly carbohydrate substances bound to small protein cores—are loosely attached to the outer surface of the cell as well. Thus, the entire outside surface of the cell often has a loose carbohydrate coat called the glycocalyx.

The carbohydrate moieties attached to the outer surface of the cell have several important functions:

Ribosomes and the Granular Endoplasmic Reticulum.

Attached to the outer surfaces of many parts of the endoplasmic reticulum are large numbers of minute granular particles called ribosomes. Where these particles are present, the reticulum is called the granular endoplasmic reticulum. The ribosomes are composed of a mixture of RNA and proteins, and they function to synthesize new protein molecules in the cell, as discussed later in this chapter and in Chapter 3.

Agranular Endoplasmic Reticulum.

Part of the endoplasmic reticulum has no attached ribosomes. This part is called the agranular or smooth, endoplasmic reticulum. The agranular reticulum functions for the synthesis of lipid substances and for other processes of the cells promoted by intrareticular enzymes.

Nuclear Membrane.

The nuclear membrane, also called the nuclear envelope, is actually two separate bilayer membranes, one inside the other. The outer membrane is continuous with the endoplasmic reticulum of the cell cytoplasm, and the space between the two nuclear membranes is also continuous with the space inside the endoplasmic reticulum, as shown in Figure 2-9.

The nuclear membrane is penetrated by several thousand nuclear pores. Large complexes of protein molecules are attached at the edges of the pores so that the central area of each pore is only about 9 nanometers in diameter. Even this size is large enough to allow molecules up to 44,000 molecular weight to pass through with reasonable ease.

Nucleoli and Formation of Ribosomes.

The nuclei of most cells contain one or more highly staining structures called nucleoli. The nucleolus, unlike most other organelles discussed here, does not have a limiting membrane. Instead, it is simply an accumulation of large amounts of RNA and proteins of the types found in ribosomes. The nucleolus becomes considerably enlarged when the cell is actively synthesizing proteins.

Formation of the nucleoli (and of the ribosomes in the cytoplasm outside the nucleus) begins in the nucleus. First, specific DNA genes in the chromosomes cause RNA to be synthesized. Some of this synthesized RNA is stored in the nucleoli, but most of it is transported outward through the nuclear pores into the cytoplasm. Here it is used in conjunction with specific proteins to assemble “mature” ribosomes that play an essential role in forming cytoplasmic proteins, as discussed more fully in Chapter 3.

Pinocytosis.

Pinocytosis occurs continually in the cell membranes of most cells, but it is especially rapid in some cells. For instance, it occurs so rapidly in macrophages that about 3 percent of the total macrophage membrane is engulfed in the form of vesicles each minute. Even so, the pinocytotic vesicles are so small—usually only 100 to 200 nanometers in diameter—that most of them can be seen only with an electron microscope.

Pinocytosis is the only means by which most large macromolecules, such as most protein molecules, can enter cells. In fact, the rate at which pinocytotic vesicles form is usually enhanced when such macromolecules attach to the cell membrane.

Figure 2-11 demonstrates the successive steps of pinocytosis, showing three molecules of protein attaching to the membrane. These molecules usually attach to specialized protein receptors on the surface of the membrane that are specific for the type of protein that is to be absorbed. The receptors generally are concentrated in small pits on the outer surface of the cell membrane, called coated pits. On the inside of the cell membrane beneath these pits is a latticework of fibrillar protein called clathrin, as well as other proteins, perhaps including contractile filaments of actin and myosin. Once the protein molecules have bound with the receptors, the surface properties of the local membrane change in such a way that the entire pit invaginates inward and the fibrillar proteins surrounding the invaginating pit cause its borders to close over the attached proteins, as well as over a small amount of extracellular fluid. Immediately thereafter, the invaginated portion of the membrane breaks away from the surface of the cell, forming a pinocytotic vesicle inside the cytoplasm of the cell.

What causes the cell membrane to go through the necessary contortions to form pinocytotic vesicles is still unclear. This process requires energy from within the cell, which is supplied by ATP, a high-energy substance discussed later in this chapter. This process also requires the presence of calcium ions in the extracellular fluid, which probably react with contractile protein filaments beneath the coated pits to provide the force for pinching the vesicles away from the cell membrane.

Phagocytosis.

Phagocytosis occurs in much the same way as pinocytosis occurs, except that it involves large particles rather than molecules. Only certain cells have the capability of phagocytosis, most notably the tissue macrophages and some white blood cells.

Phagocytosis is initiated when a particle such as a bacterium, a dead cell, or tissue debris binds with receptors on the surface of the phagocyte. In the case of bacteria, each bacterium is usually already attached to a specific antibody, and it is the antibody that attaches to the phagocyte receptors, dragging the bacterium along with it. This intermediation of antibodies is called opsonization, which is discussed in Chapters 34 and 35.

Phagocytosis occurs in the following steps:

Regression of Tissues and Autolysis of Damaged Cells.

Tissues of the body often regress to a smaller size. For instance, this regression occurs in the uterus after pregnancy, in muscles during long periods of inactivity, and in mammary glands at the end of lactation. Lysosomes are responsible for much of this regression.

Another special role of the lysosomes is removal of damaged cells or damaged portions of cells from tissues. Damage to the cell—caused by heat, cold, trauma, chemicals, or any other factor—induces lysosomes to rupture. The released hydrolases immediately begin to digest the surrounding organic substances. If the damage is slight, only a portion of the cell is removed and the cell is then repaired. If the damage is severe, the entire cell is digested, a process called autolysis. In this way, the cell is completely removed and a new cell of the same type ordinarily is formed by mitotic reproduction of an adjacent cell to take the place of the old one.

The lysosomes also contain bactericidal agents that can kill phagocytized bacteria before they can cause cellular damage. These agents include (1) lysozyme, which dissolves the bacterial cell wall; (2) lysoferrin, which binds iron and other substances before they can promote bacterial growth; and (3) acid at a pH of about 5.0, which activates the hydrolases and inactivates bacterial metabolic systems.

Recycling of Cell Organelles—Autophagy.

Lysosomes play a key role in the process of autophagy, which literally means “to eat oneself.” Autophagy is a housekeeping process by which obsolete organelles and large protein aggregates are degraded and recycled (Figure 2-13). Worn-out cell organelles are transferred to lysosomes by double membrane structures called autophagosomes that are formed in the cytosol. Invagination of the lysosomal membrane and the formation of vesicles provides another pathway for cytosolic structures to be transported into the lumen of the lysosomes. Once inside the lysosomes, the organelles are digested and the nutrients are reused by the cell. Autophagy contributes to the routine turnover of cytoplasmic components and is a key mechanism for tissue development, for cell survival when nutrients are scarce, and for maintaining homeostasis. In liver cells, for example, the average mitochondrion normally has a life span of only about 10 days before it is destroyed.

Processing of Endoplasmic Secretions by the Golgi Apparatus—Formation of Vesicles.

Figure 2-14 summarizes the major functions of the endoplasmic reticulum and Golgi apparatus. As substances are formed in the endoplasmic reticulum, especially the proteins, they are transported through the tubules toward portions of the smooth endoplasmic reticulum that lie nearest the Golgi apparatus. At this point, small transport vesicles composed of small envelopes of smooth endoplasmic reticulum continually break away and diffuse to the deepest layer of the Golgi apparatus. Inside these vesicles are the synthesized proteins and other products from the endoplasmic reticulum.

The transport vesicles instantly fuse with the Golgi apparatus and empty their contained substances into the vesicular spaces of the Golgi apparatus. Here, additional carbohydrate moieties are added to the secretions. Also, an important function of the Golgi apparatus is to compact the endoplasmic reticular secretions into highly concentrated packets. As the secretions pass toward the outermost layers of the Golgi apparatus, the compaction and processing proceed. Finally, both small and large vesicles continually break away from the Golgi apparatus, carrying with them the compacted secretory substances, and in turn, the vesicles diffuse throughout the cell.

The following example provides an idea of the timing of these processes: When a glandular cell is bathed in radioactive amino acids, newly formed radioactive protein molecules can be detected in the granular endoplasmic reticulum within 3 to 5 minutes. Within 20 minutes, newly formed proteins are already present in the Golgi apparatus, and within 1 to 2 hours, the proteins are secreted from the surface of the cell.

Types of Vesicles Formed by the Golgi Apparatus—Secretory Vesicles and Lysosomes.

In a highly secretory cell, the vesicles formed by the Golgi apparatus are mainly secretory vesicles containing protein substances that are to be secreted through the surface of the cell membrane. These secretory vesicles first diffuse to the cell membrane, then fuse with it and empty their substances to the exterior by the mechanism called exocytosis. Exocytosis, in most cases, is stimulated by the entry of calcium ions into the cell; calcium ions interact with the vesicular membrane in some way that is not understood and cause its fusion with the cell membrane, followed by exocytosis—that is, opening of the membrane's outer surface and extrusion of its contents outside the cell. Some vesicles, however, are destined for intra­cellular use.

Use of Intracellular Vesicles to Replenish Cellular Membranes.

Some of the intracellular vesicles formed by the Golgi apparatus fuse with the cell membrane or with the membranes of intracellular structures such as the mitochondria and even the endoplasmic reticulum. This fusion increases the expanse of these membranes and thereby replenishes the membranes as they are used up. For instance, the cell membrane loses much of its substance every time it forms a phagocytic or pinocytotic vesicle, and the vesicular membranes of the Golgi apparatus continually replenish the cell membrane.

In summary, the membranous system of the endoplasmic reticulum and Golgi apparatus represents a highly metabolic organ capable of forming new intracellular structures, as well as secretory substances to be extruded from the cell.

About 95 percent of the cell's ATP formation occurs in the mitochondria. The pyruvic acid derived from carbohydrates, fatty acids from lipids, and amino acids from proteins is eventually converted into the compound acetyl-coenzyme A (CoA) in the matrix of mitochondria. This substance, in turn, is further dissoluted (for the purpose of extracting its energy) by another series of enzymes in the mitochondrion matrix, undergoing dissolution in a sequence of chemical reactions called the citric acid cycle, or Krebs cycle. These chemical reactions are so important that they are explained in detail in Chapter 68.

In this citric acid cycle, acetyl-CoA is split into its component parts, hydrogen atoms and carbon dioxide. The carbon dioxide diffuses out of the mitochondria and eventually out of the cell; finally, it is excreted from the body through the lungs.

The hydrogen atoms, conversely, are highly reactive, and they combine with oxygen that has also diffused into the mitochondria. This combination releases a tremendous amount of energy, which is used by the mitochondria to convert large amounts of ADP to ATP. The processes of these reactions are complex, requiring the participation of many protein enzymes that are integral parts of mitochondrial membranous shelves that protrude into the mitochondrial matrix. The initial event is removal of an electron from the hydrogen atom, thus converting it to a hydrogen ion. The terminal event is combination of hydrogen ions with oxygen to form water plus release of tremendous amounts of energy to large globular proteins that protrude like knobs from the membranes of the mitochondrial shelves; these proteins are called ATP synthetase. Finally, the enzyme ATP synthetase uses the energy from the hydrogen ions to cause the conversion of ADP to ATP. The newly formed ATP is transported out of the mitochondria into all parts of the cell cytoplasm and nucleoplasm, where its energy is used to energize multiple cell functions.

This overall process for formation of ATP is called the chemiosmotic mechanism of ATP formation. The chemical and physical details of this mechanism are presented in Chapter 68, and many of the detailed metabolic functions of ATP in the body are presented in Chapters 68 through 72.

Uses of ATP for Cellular Function.

Energy from ATP is used to promote three major categories of cellular functions: (1) transport of substances through multiple membranes in the cell, (2) synthesis of chemical compounds throughout the cell, and (3) mechanical work. These uses of ATP are illustrated by examples in Figure 2-16: (1) to supply energy for the transport of sodium through the cell membrane, (2) to promote protein synthesis by the ribosomes, and (3) to supply the energy needed during muscle contraction.

In addition to membrane transport of sodium, energy from ATP is required for membrane transport of potassium ions, calcium ions, magnesium ions, phosphate ions, chloride ions, urate ions, hydrogen ions, and many other ions and various organic substances. Membrane transport is so important to cell function that some cells—the renal tubular cells, for instance—use as much as 80 percent of the ATP that they form for this purpose alone.

In addition to synthesizing proteins, cells make phospholipids, cholesterol, purines, pyrimidines, and a host of other substances. Synthesis of almost any chemical compound requires energy. For instance, a single protein molecule might be composed of as many as several thousand amino acids attached to one another by peptide linkages. The formation of each of these linkages requires energy derived from the breakdown of four high-energy bonds; thus, many thousand ATP molecules must release their energy as each protein molecule is formed. Indeed, some cells use as much as 75 percent of all the ATP formed in the cell simply to synthesize new chemical compounds, especially protein molecules; this is particularly true during the growth phase of cells.

The final major use of ATP is to supply energy for special cells to perform mechanical work. We see in Chapter 6 that each contraction of a muscle fiber requires expenditure of tremendous quantities of ATP energy. Other cells perform mechanical work in other ways, especially by ciliary and ameboid motion, described later in this chapter. The source of energy for all these types of mechanical work is ATP.

In summary, ATP is always available to release its energy rapidly and almost explosively wherever in the cell it is needed. To replace the ATP used by the cell, much slower chemical reactions break down carbohydrates, fats, and proteins and use the energy derived from these processes to form new ATP. More than 95 percent of this ATP is formed in the mitochondria, which accounts for the mitochondria being called the “powerhouses” of the cell.

Mechanism of Ameboid Locomotion.

Figure 2-17 shows the general principle of ameboid motion. Basically, it results from continual formation of new cell membrane at the leading edge of the pseudopodium and continual absorption of the membrane in mid and rear portions of the cell. Two other effects are also essential for forward movement of the cell. The first effect is attachment of the pseudopodium to surrounding tissues so that it becomes fixed in its leading position, while the remainder of the cell body is pulled forward toward the point of attachment. This attachment is effected by receptor proteins that line the insides of exocytotic vesicles. When the vesicles become part of the pseudopodial membrane, they open so that their insides evert to the outside, and the receptors now protrude to the outside and attach to ligands in the surrounding tissues.

At the opposite end of the cell, the receptors pull away from their ligands and form new endocytotic vesicles. Then, inside the cell, these vesicles stream toward the pseudopodial end of the cell, where they are used to form new membrane for the pseudopodium.

The second essential effect for locomotion is to provide the energy required to pull the cell body in the direction of the pseudopodium. In the cytoplasm of all cells is a moderate to large amount of the protein actin. Much of the actin is in the form of single molecules that do not provide any motive power; however, these molecules polymerize to form a filamentous network, and the network contracts when it binds with an actin-binding protein such as myosin. The entire process is energized by the high-energy compound ATP. This mechanism is what happens in the pseudopodium of a moving cell, where such a network of actin filaments forms anew inside the enlarging pseudopodium. Contraction also occurs in the ectoplasm of the cell body, where a preexisting actin network is already present beneath the cell membrane.

Types of Cells That Exhibit Ameboid Locomotion.

The most common cells to exhibit ameboid locomotion in the human body are the white blood cells when they move out of the blood into the tissues to form tissue macrophages. Other types of cells can also move by ameboid locomotion under certain circumstances. For instance, fibroblasts move into a damaged area to help repair the damage, and even the germinal cells of the skin, although ordinarily completely sessile cells, move toward a cut area to repair the opening. Finally, cell locomotion is especially important in the development of the embryo and fetus after fertilization of an ovum. For instance, embryonic cells often must migrate long distances from their sites of origin to new areas during development of special structures.

Control of Ameboid Locomotion—Chemotaxis.

The most important initiator of ameboid locomotion is the process called chemotaxis, which results from the appearance of certain chemical substances in the tissues. Any chemical substance that causes chemotaxis to occur is called a chemotactic substance. Most cells that exhibit ameboid locomotion move toward the source of a chemotactic substance—that is, from an area of lower concentration toward an area of higher concentration—which is called positive chemotaxis. Some cells move away from the source, which is called negative chemotaxis.

But how does chemotaxis control the direction of ameboid locomotion? Although the answer is not certain, it is known that the side of the cell most exposed to the chemotactic substance develops membrane changes that cause pseudopodial protrusion.

Mechanism of Ciliary Movement.

Although not all aspects of ciliary movement are known, we are aware of the following elements: First, the nine double tubules and the two single tubules are all linked to one another by a complex of protein cross-linkages; this total complex of tubules and cross-linkages is called the axoneme. Second, even after removal of the membrane and destruction of other elements of the cilium besides the axoneme, the cilium can still beat under appropriate conditions. Third, two conditions are necessary for continued beating of the axoneme after removal of the other structures of the cilium: (1) the availability of ATP and (2) appropriate ionic conditions, especially appropriate concentrations of magnesium and calcium. Fourth, during forward motion of the cilium, the double tubules on the front edge of the cilium slide outward toward the tip of the cilium, while those on the back edge remain in place. Fifth, multiple protein arms composed of the protein dynein, which has adenosine triphosphatase (ATPase) enzymatic activity, project from each double tubule toward an adjacent double tubule.

Given this basic information, it has been determined that the release of energy from ATP in contact with the ATPase dynein arms causes the heads of these arms to “crawl” rapidly along the surface of the adjacent double tubule. If the front tubules crawl outward while the back tubules remain stationary, bending occurs.

The way in which cilia contraction is controlled is not understood. The cilia of some genetically abnormal cells do not have the two central single tubules, and these cilia fail to beat. Therefore, it is presumed that some signal, perhaps an electrochemical signal, is transmitted along these two central tubules to activate the dynein arms.