The Human Body: Linking Structure and Function

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Chapter 1

Cells

Abstract

The cell is the fundamental unit of life. A typical cell consists of a nucleus, cytoplasm, and a surrounding plasma membrane. The nucleus contains the DNA, which contains the genetic information needed to form a protein through the mediation of messenger RNA (mRNA) and transfer RNA (tRNA). The rough endoplasmic reticulum (RER) and Golgi apparatus within the cytoplasm take part in the final processing steps in protein synthesis. Within the cytoplasm, mitochondria provide energy and lysosomes are involved in the breakdown of larger molecules for further processing. Cytoskeletal elements are involved in both the support and movements of a cell. Specializations of the plasma membrane mediate intercellular communication and the passage of materials in and out of the cell. Cellular division is part of a tightly controlled cell cycle.

Keywords

Cell; plasma membrane; membrane transport; nucleus; cytoplasm; endoplasmic reticulum; Golgi apparatus; lysosomes; mitochondria; cytoskeleton; cell division; cell cycle

The cell is a fundamental unit of life. Many organisms consist of only a single cell, which is adequate for all physiological functions, including reproduction. Most plants and animals, however, are made up of enormous numbers of cells, which work in community. Not all cells are alike. The mature human body contains an estimated 200+ types of cells, each of which is specialized to fulfill a different function. Aggregates of similar cells form tissues and organs that seamlessly accommodate our functional needs. The number of cells that collectively constitute the human body is staggering. A recent careful estimate places that number at ~37.2 trillion.

Even more staggering is the number of co-inhabitants in our bodies—the bacteria and other microorganisms that constitute our microbiome. The bacteria, which may be 10 times as numerous as all the other cells of the body combined, share our body space in a mutually beneficial (symbiotic) relationship. All body surfaces that directly connect with the outside, for example, skin, digestive system, vagina, are home to significant populations of bacteria. Until very recently it has been assumed that our internal tissues are sterile, but bacteria are now being found in many tissues that are carefully analyzed.

In its most elemental representation, a cell consists of a nucleus surrounded by cytoplasm and is bounded on the outside by a thin plasma membrane. Each of these three is highly complex and contains many components. The nucleus is a repository for the genetic information that guides much of development and function. The plasma membrane serves as a gatekeeper that controls what comes into and what leaves the cell. Filling in the space between the nucleus and the plasma membrane, the cytoplasm contains a large number of internal structures (organelles), each of which serves functions as diverse as breaking down molecules and providing energy.

Despite their great variety, most cells are composed of a common set of organelles, but as cells specialize during development, certain sets of organelles that contribute to their particular function assume prominence. For example, muscle cells assemble arrays of contractile proteins that allow them to shorten upon demand, whereas islet cells of the pancreas develop the cellular infrastructure needed to synthesize and secrete insulin.

The aim of this chapter is to provide a general introduction to cellular structure and function. In order to provide a basic vocabulary, it outlines the most important structures found within cells and their roles in generic cellular functions (Fig. 1.1). The biology of many specific cell types will be covered later in the text, in the context of discussions of the organ systems in which they reside.

Figure 1.1 The major constituents of a generic mammalian cell. From Pollard and Earnshaw (2004), with permission.

The Plasma Membrane

The plasma membrane is not only a container for the contents, but it determines what passes in and out of the cell. Adjacent cells are joined to one another through specific cell adhesion molecules located on the surfaces of the plasma membranes. The plasma membrane also receives signals from its immediate environment that are transmitted to the interior of the cell, which then responds to the signals.

In essence, the plasma membrane consists of a lipid bilayer studded with a large variety of proteins, which play a variety of roles in the life of a cell (Fig. 1.2). About 50% of the plasma membrane is lipid, and the other 50% is protein. Some of the proteins are attached to either surface of the plasma membrane; others pass completely through it. Still others form channels of various sorts that allow the passage of water and a variety of solutes (ions and small molecules) through the membrane in either direction.

Figure 1.2 Types of molecules embedded in cell membranes. Cholesterol molecules are inserted within the lipid bilayer. Various types of proteins may extend entirely through the cell membrane or be partially inserted in the outer or inner face. Complex carbohydrates are often attached to membrane proteins or to the membrane itself. From Carroll (2007), with permission.

Lipid Bilayer

The lipid bilayer, which forms the framework of the plasma membrane, consists of two layers of phospholipid molecules. Each phospholipid molecule is shaped like a clothespin, with two fatty acids (the lipid) constituting the prongs and a combination of glycerol and phosphoric acid making up the head (see Fig. 1.2). Imagine two rows of these molecular clothespins, in which each layer lie side by side with the heads facing outward and the prongs facing inward. The fatty acid prongs are hydrophobic (do not mix with water), whereas the heads are hydrophilic and can interact with the watery fluids on either side of the membrane.

The plasma membrane contains a number of other forms of lipids, but in lesser amounts. Some of these molecules are connected with carbohydrate chains that protrude from the surface of the cell. The various carbohydrate chains on the outer surface form a fuzzy coat, often known as the glycocalyx. The glycocalyx of specific cell types, species and even individuals is unique, and it is a major contributor to the immunological identity of the cell and the individual (see Chapter 8). Human blood types (A, B, AB and O) are a reflection of biochemical differences in the glycocalyces of blood cells from different individuals.

An important internal component of the plasma membrane (~20% of plasma membrane lipids) is cholesterol, which stiffens the membranes by serving as anchors for the other molecules, but in higher concentrations actually contributes to the fluidity of the molecules within the membrane. Membrane fluidity is important in healing microwounds in the plasma membrane. At a practical level, this property allows one to puncture the plasma membrane to remove the nucleus from an egg and to introduce a new one into it, as is done in cloning experiments. In the field of reproductive medicine, the introduction of a sperm directly into an egg is one method for achieving in vitro fertilization. Even in normal fertilization, the plasma membrane of the sperm fuses with that of the egg as the sperm enters.

Plasma Membrane Proteins

Embedded within the plasma membrane are several categories of proteins, which serve many cellular functions (Table 1.1). Although the protein molecules themselves are stable, the membrane as a whole is a very dynamic structure, with the configuration of the lipid and protein molecules constantly changing. An early representation of membrane physiology was called the fluid mosaic model, in which the lipid component of the membrane was viewed as the surface of a soup with embedded protein molecules floating within it like dumplings. We now know that membrane physiology is much more complex than that and that strong connections exist between membrane proteins and some of the molecules located both inside and outside the cell. Nevertheless, membrane fluidity is real, and both protein and phospholipid molecules can often move freely within the plasma membrane.

Table 1.1

Of the several categories of membrane proteins (see Fig. 1.2), one variety, integral proteins, consists of thousands of different types of proteins that are attached to the inner or outer surfaces of the plasma membrane or that pass completely through the membrane. These proteins have numerous functions. Some, called receptors, protrude from the outer surface and bind to signal molecules coming from other cells. After the binding event, the configuration of the receptor molecule typically changes. This change is then communicated to a series of proteins on the inside of the membrane, which are part of a second messenger (signal transduction) system that passes the signal through the cytoplasm to the nucleus, where it stimulates the expression of a gene within the DNA. Other integral proteins act principally as enzymes that break down molecules at the cell surface. For example, in the small intestine, they carry out the last stages of breakdown of carbohydrate and protein digestion. On muscle fibers, the membrane-bound enzyme cholinesterase breaks down the neurotransmitter acetylcholine (see p. 117) so that it does not continue to stimulate contraction of the muscle fiber long after it receives a signal from the nerve to contract.

Many intrinsic proteins contain carbohydrate chains that contribute to the immunological identity of the cell. Still others promote intercellular adhesion as they form stable bonds with other molecules of the same type on neighboring cells. One class of cell adhesion molecules (the Ig-CAMs) consists of members of the immunoglobulin family (see p. 215). Such adhesion molecules bind directly to other molecules of the same type on the next cell. Another large class of adhesion molecules, the cadherins, utilizes Ca++ as a binding agent between the two cadherins on opposite cell membranes.

Channels, Pumps, and Carriers

Most of the remaining membrane proteins are involved in the transport of materials across biological membranes (Fig. 1.3). There are three main categories of such proteins. The first category of membrane transport proteins is membrane channels, which allow the free transport of ions or small molecules along concentration gradients leading toward either the inside or the outside of the cell. These do not require great amounts of energy for their normal function. Membrane channels exist in a large variety of sizes and shapes, but their most important characteristic is that they allow the passage of both water and solutes through the cell membrane much faster than any other means. This is important in organs, such as the kidney, where large amounts of both water and ions must be continually processed in short amounts of time. Some channels are gated, meaning that part of the protein acts as a plug that opens or closes the channel depending upon the configuration of the protein. Gated channels in a nerve fiber allow the passage of Na+ through the plasma membrane in a very short period of time (measured in milliseconds). Such rapid transport of Na+ is required to generate an action potential, which serves as the basis of a nerve impulse (see p. 59). Channels specific for the passage of water are lined by aquaporin proteins. Although water molecules can diffuse through the phospholipid component of the plasma membrane, such passage is slow. Aquaporins allow very rapid transit of H2O through the membrane.

Figure 1.3 Upper row—Various means by which water and/or ions can be transported across a cell membrane. Lower row—Different means of ion or small molecule transport via membrane carriers across a cell membrane through channels with different properties.

Another variety of membrane protein forms membrane pumps (see Fig. 1.3). These pumps must utilize energy from one of several sources in order to function. The most common source of energy is the hydrolysis of ATP (adenosine triphosphate—the main source of internal energy in biological systems) into ADP (adenosine diphosphate) + phosphate, with the concomitant release of energy from the broken phosphate bond. In some systems, such as the eye, even light can serve as the source of energy. All cells have thousands of Na+–K+ ATPase pumps in their plasma membranes. Close to half of the ATP-derived energy used by a cell is used to power membrane pumps, which work almost continuously. The most important feature of membrane pumps is that they can transport materials up a concentration gradient—which is why so much energy is required. This advantage counters their intrinsic disadvantage, in that the overall flow of transport via pumps is considerably slower than that seen in channels. Nevertheless, things can be accomplished by means of pumps that cannot be done through channels. A good example is the inside of the stomach, where certain cells secrete hydrochloric acid in such concentrations that the pH can be as low as 1.0. A neutral pH is 7.0, and each pH point is a degree of magnitude greater than the previous one. Thus a pH of 1.0 is six degrees of magnitude greater than neutral (or 1,000,000 times as concentrated). Such a degree of concentration represents the upper limit of a membrane pump, but that alone is impressive.

The third category of transport proteins is membrane carriers (see Fig. 1.3). Although seemingly similar to channels and pumps, membrane carriers have a wide repertoire of functions. Some, called uniporters, provide low-resistance pathways for the transportation of simple sugars and amino acids into cells. Others, called symporters, are able to transport two or more kinds of simple molecules across a membrane at the same time. Still others, called antiporters, can drive an ion in one direction and another ion or molecule in the opposite direction. Some carrier proteins function by binding to a solute on one side of a membrane and then changing their configuration. As the configuration of the carrier protein is changing, the bound solute is brought to the other side of the membrane and then released. Insulin stimulates the insertion into the plasma membrane of many carrier proteins that bring glucose into cells.

Specialized portions of plasma membranes are used to hold cells together and to inhibit the passage of fluid and solutes between cells. Another type of membrane specialization, the gap junction, facilitates rapid communication between two cells. These specializations are discussed on p. 30 in the context of epithelial functions because they are most prominently represented in epithelia.

The Nucleus

If the plasma membrane represents the gatekeeper of a cell, the nucleus (Fig. 1.4) represents the information library and server, because almost all of the genetic information of the individual is embedded in the DNA of the chromosomes. Upon appropriate processing of signals both intrinsic and extrinsic to the cell, the nucleus then unlocks specific bits of genetic information and produces molecular messages that are later acted on by other components of the cell.

Figure 1.4 (A). Light micrograph of liver cells (hepatocytes), illustrating the appearance of the nucleus (purple) and cytoplasm (pink). (B). Electron micrograph of the nucleus of a cell, showing a large nucleolus and nuclear chromatin (condensed chromosomal material). The inset shows a nuclear pore, through which molecules enter and leave the nucleus. (A) From Erlandsen and Magney (1992), with permission. (B) From Pollard and Earnshaw (2004), with permission.

The heart of the nucleus is the set of 23 pairs of chromosomes, which are the repository of the genetic information. The genetic information in the roughly 20,000–25,000 genes in the human genome is contained in the DNA (deoxyribonucleic acid) strands that form the core of the chromosome (Fig. 1.5). In any chromosome, the DNA exists as a coiled double helical structure composed of repeating units of four nucleotide bases adenine (A), cytosine (C), guanine (G), and thymine (T) in two strands of DNA. A single nucleotide consists of three components—a base, a sugar, and a phosphate group. For each nucleotide, the sugar (deoxyribose) and the phosphate group are the same. Like rungs of a ladder, the bases of the two DNA strands connect through chemical bonds in a very specific manner, so that only A and T or C and G can be bound together (see Fig. 1.8). A–Ts or C–Gs are called base pairs, and a human nucleus contains about 3 × 10⁹ base pairs.

Figure 1.5 A chromosome, showing different levels of organization from a condensed chromosome containing two joined chromatids (bottom), as seen at the time of a mitotic division, down to the double helix of a DNA molecule. bp—base pair; nm—nanometer. From Adkison (2012), with permission.

The DNA strands are very long and if laid end-to-end, the total amount of DNA in the nucleus would exceed 6 m in length. Packaging the DNA so that it will both fit into the nucleus and remain functional is complex. The first step is wrapping the DNA around several million tiny aggregates of eight small proteins called histones to form structures called nucleosomes. The DNA wraps itself roughly twice around each nucleosome, with some unwrapped (naked) DNA remaining between the nucleosomes, much like the string and beads of a necklace (see Fig. 1.5). This arrangement reduces the overall length of the DNA by roughly a factor of seven. Further packaging consists of folding of the necklace-like DNA strands, which reduces the overall length of the DNA by 40-fold. On top of that, additional folding and then a great deal of looping compresses the DNA to the point where it will fit into the nucleus. Despite all the compaction, the chromosomes within a resting nucleus are not identifiable as individual structures at the light microscopic level, although their presence is indicated by strands and clumps of stained material called chromatin. The fine strands of DNA, called euchromatin, are the most active, whereas the clumps (heterochromatin) represent inactive forms of DNA (see Fig. 1.4). Roughly 10% of the nuclear DNA is represented as euchromatin, and 90% is in the heterochromatin form. Only when a cell is preparing to divide, do the chromosomes further condense and become readily recognizable as individual entities (Fig. 1.6).

Figure 1.6 Condensed human chromosomes at the time of a mitotic division. (A) Individual chromosomes are matched with their homologous pair. They are arranged from the largest to the smallest and are assigned numbers. This chromosomal spread is from a male, and the X and Y chromosomes are quite different. (B) Spectral karyotyping and fluorescence in situ hybridization of human chromosomes. These techniques allow color-coding of individual chromosomes. (A) From Jorde et al. (2010), with permission. (B) From Waugh and Grant (2014), with permission.

The chromosomes are contained within the nuclear envelope, which is a double membrane that is penetrated by many nuclear pores (see Fig. 1.4B) large enough to permit the passage of proteins and RNAs through the nuclear envelope. Nuclear pores are about 10 times the diameter of membrane channels, but protein meshworks across the pores control to some extent what passes through them. Within the nucleus, in addition to the chromosomes, is a prominent structure called the nucleolus (see Fig. 1.4). The nucleolus, which looks like a dark spot at the light microscopic level, is the site where ribosomal RNA (rRNA) molecules are synthesized and then assembled into ribosomes (see p. 11). Cells with prominent nucleoli are active in ribosome production, whereas in cells not actively producing RNAs or proteins the nucleolus is much less conspicuous. Because of their considerable activity in protein production, liver and developing muscle cells have prominent nucleoli.

The Cytoplasm

Organelles

If the plasma membrane represents the gatekeeper of a cell and the nucleus the information repository, then the cytoplasm would be analogous to the workshop, where things are made and broken down. The cytoplasm contains many organelles (see Fig. 1.1). Most cells contain almost all of the types of organelles, but their amounts and distribution vary considerably and reflect the locations and functions of the cells.

Production of materials within the cytoplasm begins with protein synthesis, and protein synthesis starts with molecules of messenger RNA (mRNA) in association with ribosomes (Box 1.1). The synthesis of proteins on an mRNA template is called translation. Although the molecular mechanics are essentially the same, protein synthesis follows two cellular pathways, depending upon whether the newly synthesized proteins will remain within the cell or if they are destined for export. Intracellular proteins are made on polysomes—aggregates of free ribosomes in conjunction with mRNAs. Proteins destined for export, on the other hand, are synthesized in the rough endoplasmic reticulum (RER), which is a component of the endoplasmic reticulum.

Box 1.1

Protein Synthesis

Synthesis of a protein begins in the nucleus, with a gene located along one of the DNA strands (Fig. 1.7). A gene is represented by a long series of nucleotides (Fig. 1.8), much like cars of a train, which carry specific information in what is called the genetic code. The information within the gene is transcribed to mRNA, which serves as the template for the synthesis of a protein. The sequence of amino acids within the protein precisely reflects the information carried in sequence of nucleotides within the gene.

Proteins consist of long strings of ~20 different amino acids. Each amino acid is represented by a series of three nucleotides (triplets) in both the DNA and RNA called codons. Through the codons, there is direct continuity between the sequence of nucleotides from DNA through mRNA to the amino acid sequence of a protein. The codons form the basis for the genetic code, which in total represents the 64 possible combinations of triplets of the four nucleotides (Fig. 1.9). For example, the DNA code for the amino acid methionine is TAC (the RNA code is AUG, see below). Other amino acids may be encoded by up to six different codons (triplets), but no codon encodes more than one amino acid. To complicate things further, RNA is organized in a slightly different manner from DNA. Whereas in DNA the bases are A, T, C, G, the T (thymidine) in DNA is represented in RNA by the nucleotide uridine (U) which, like T in DNA, can bind to the base A. Thus instead of the DNA code TAC, the RNA code for methionine is AUG. A string of nucleotide triplets, each representing a different amino acid, is the information base for forming a protein. (Another difference between DNA and RNA is the sugar component, which is deoxyribose in DNA and ribose in RNA.)

At any given moment, almost all genes in a cell are inactive (turned off). Genes are inactivated by a variety of complex mechanisms, but commonly by molecules that block access to the gene. The first step in protein synthesis is to turn on the gene in question through one of a variety of molecular mechanisms. This process often begins when a protein, called a transcription factor, binds to a segment of uncoiled DNA adjacent to the gene in question and effectively turns the gene on. The stage is now set for transcription of the gene, which involves the formation of a strand of RNA (in this example, mRNA) from the DNA template that constitutes the gene.

RNA synthesis involves three stages—initiation, elongation, and termination. Initiation involves exposing the DNA segment constituting the gene so that a molecule of mRNA can be formed on the nucleotide template of the gene. In order for transcription to occur, not only must any protein molecules blocking access to the DNA be removed, but also the double helix of DNA itself must open up so that the mRNA can form along the split rungs of one strand of the DNA helix.

The key to transcription is an enzyme called RNA polymerase, which opens up the DNA double helix about 17 nucleotide pairs at a time and then facilitates the binding of complementary nucleotides to the open half-rungs of the exposed DNA (Fig. 1.10). For example, if the nucleotides CATG of the DNA were exposed, then the complementary nucleotides GUAC would be bound to the DNA in the form of a nascent RNA molecule. (Remember that in RNA, U is substituted for the T in DNA.) Thus the U of RNA binds to the A of DNA.) Addition of nucleotides to the mRNA chain constitutes the elongation phase. Like so many biochemical processes, RNA formation occurs at lightning speed, with the RNA chain elongating at a rate of 20–30 nucleotides per second. When the mRNA molecule has fully formed, the RNA polymerase reaches a termination sequence of DNA that causes the RNA polymerase to detach from both the newly formed mRNA molecule and the DNA strand. After release from the DNA and some processing, the mRNA is then transported through the nuclear pores into the cytoplasm.

Despite the fact that there are only 20,000–25,000 genes in the human genome, the human body contains hundreds of thousands of different proteins. Such a disparity is possible because of alternative splicing of mRNA. The basis for alternative splicing lies in the organization of a gene (Fig. 1.11). The length of a gene in a DNA strand consists of coding regions, called exons, and noncoding regions, called introns. In order to make a functional mRNA molecule, the introns must be enzymatically removed from the newly formed mRNA and the exons joined together. In cases where there are multiple introns, the remaining exons, carrying the information for the construction of specific protein molecules, can be spliced together in various ways. Thus if a given gene has 5 or 6 exons, there are many ways in which they can be recombined to code for a protein.

Once it has left the nucleus and has entered the cytoplasm, the mRNA molecule then becomes associated with ribosomes in preparation for the next phase of protein synthesis—translation. Here the genetic information, now encoded in the mRNA molecule, is translated, much like a language, from a series of nucleotides to a series of connected amino acids, which constitute the backbone of the protein molecule. As explained more fully elsewhere in the text, translation can occur freely in the cytoplasm or can be connected with the RER.

Translation involves three essential elements—mRNA, ribosomes and transfer RNAs (tRNA) (see Fig. 1.7). In essence, a ribosome binds to the mRNA molecule. Amino acids are brought to that site by tRNAs, and the formation of a polypeptide chain (the backbone of a protein) is initiated. As amino acids are added to the chain, the mRNA passes through the ribosome in a manner analogous to a tape being pulled out from a tape measure.

Even at the electron microscopic level, ribosomes look like small dots, but in reality, they are very complex structures. A single ribosome is composed of two subunits (large and small) containing several types of rRNA molecules and over 80 different proteins. Initially, the end of an mRNA molecule, called the leader sequence, attaches to a special binding site of a small subunit of the ribosome. Then a special initiator tRNA attaches to the start codon on the mRNA, which is always AUG, the codon for the amino acid methionine. Finally, the large ribosomal subunit attaches to the small one to form a functional ribosomal–mRNA complex.

A key to this process is the structure and function of the tRNA molecule. To give a sense of proportionality, a tRNA molecule contains 70–90 nucleotide bases, an mRNA molecule up to 10,000 bases, and DNA up to 100 million base pairs. A tRNA molecule is shaped something like a clover leaf (Fig. 1.12). At the tip of the leaf is a series of three nucleotides that is called an anticodon. These three nucleotides are complementary to one codon of the mRNA. For example, an anticodon CCA of tRNA would bind specifically to the GGU codon of an mRNA. On the stem end of the tRNA molecule is a binding site for a specific amino acid corresponding to the codon of the mRNA and the anticodon of the tRNA. Thus for the tRNA with the anticodon CCA, the amino acid glycine, whose codon is GGU, would be attached. There are 61 possible different tRNAs, covering each of the possible amino acids. For many amino acids there exist up to six possible tRNAs because of redundancy in the code.

In the formation of a protein, a first step is binding of the anticodon end of the appropriate tRNA molecule to the corresponding codon of the mRNA (see Fig. 1.7). (As seen above, the formation of any protein begins with the codon AUG for the amino acid methionine.) Once formation of the polypeptide chain has begun, the amino acid at the stem end of the tRNA molecule becomes connected to the last amino acid formed in the growing polypeptide chain through enzymatic activity in the large subunit of the ribosome. During the process of polypeptide formation, the ribosome moves along the length of the mRNA molecule until it reaches the end. While this ribosome is en route, another ribosome attaches to the beginning of the mRNA and starts to produce another polypeptide. At any given time, several ribosomes may be attached to the same strand of mRNA. The complex of one mRNA molecule and several attached ribosomes is called a polyribosome. The process of making a polypeptide chain is repeated until the entire message in the mRNA has been read, ending with a specific termination codon. At that point, the completed polypeptide chain is released from the ribosome, and the ribosome breaks up into its subunits.

A newly minted polypeptide chain is by no means complete. Even while the polypeptide chain is being synthesized, its free end begins to fold into what will become its final three-dimensional structure.¹ In almost all cases, small pieces are snipped off from the polypeptide chain at a later time in order to activate the protein. These pieces are called signal peptides, and before they are snipped off, they help direct proteins designed for export to the appropriate export pathways in the cell. Cytosolic proteins—those designed to remain within the cell—lack signal peptides. Often carbohydrate chains are added before a protein molecule is fully complete.

¹The three-dimensional structure of a protein is a function of its amino acid sequence. Among the amino acids, biophysical interactions determine a protein’s final three-dimensional shape, and its shape is a major determinant of the functionality of any given protein.

Rough Endoplasmic Reticulum (RER)

The endoplasmic reticulum, which constitutes about 50% of the membranous surface within the cytoplasm, consists of three main regions that are involved in both synthetic and transport processes. The most prominent is the RER, which looks like a stack of flattened sacs studded with ribosomes on their outer surface (Fig. 1.13). The RER is continuous with the nuclear envelope. In fact, some cell biologists feel that the nuclear envelope arose evolutionarily as a modification of the RER. Polypeptides are synthesized on the outer surface of the RER and are then transferred into the interior of the sacs where they undergo posttranslational modifications. Folding of the polypeptide chains is probably a universal phenomenon within the sacs (cisternae) of the RER. In addition, it is common for small segments of newly formed polypeptide chains to be removed as they gradually take the form of the definitive proteins. Most proteins designed for export or inclusion into membranes add carbohydrate groups to the polypeptide backbone. For some of these proteins, the initial stages of this process occur in the RER. The modified proteins then move into a transitional region of the endoplasmic reticulum, where transfer vesicles containing the proteins, designed for export or for inclusion in membranes, bud off and are transferred to the Golgi apparatus (see Fig. 1.15).

Figure 1.7 General scheme of the steps involved in protein synthesis, starting with the DNA molecule in the nucleus and ending with the assembly of a polypeptide chain within the cytoplasm. From Turnpenny and Ellard (2012), with permission.

Figure 1.8 Structure of the DNA molecule, showing the organization of the nucleotides into individual chains of DNA, which are wrapped around each other in a double helix. A—adenosine, C—cytosine, G—guanosine, T—thymidine. Individual bases are connected to sugars (S), and the sugars are interconnected by phosphate (P) bonds. Overall, the DNA strands are organized in an antiparallel fashion. From Adkison (2012), with permission.

Figure 1.9 The genetic code. The capital letters (A, C, G, U) represent the nucleotides in an mRNA molecule Three nucleotides represent a codon. The three-letter sequences are abbreviations for names of amino acids, for example, Phe—phenylalanine; Leu—leucine. The codons represented by green and red dots are special ones that initiate and terminate polypeptide chain formation. From Pollard and Earnshaw (2004), with permission.

Figure 1.10 Transcription of DNA into mRNA through the action of RNA polymerase. mRNA nucleotides are assembled in an order complementary to that of the nucleotides in the DNA strand. From Jorde et al. (2010), with permission.

Figure 1.11 Alternative splicing, showing how different combinations of exons can be joined together to form the basis for the creation of different peptides.

Figure 1.12 Structure of a tRNA molecule. Three nucleotides at the anticodon end of the molecule attach to three nucleotides of an mRNA codon (not pictured). The other (stem) end of the molecule is the amino acid attachment site, and the amino acid attached to the tRNA is added to the end of a forming polypeptide chain. From Jorde et al. (2010), with permission.

Figure 1.13 Electron micrograph of a plasma cell, showing a massive RER (rough endoplasmic reticulum) in the cytoplasm. In plasma cells, antibodies are synthesized in the RER. From Pollard and Earnshaw (2004), with permission.

Smooth Endoplasmic Reticulum

The next region of endoplasmic reticulum is an aggregation of tubules, often branched, called the smooth endoplasmic reticulum (Fig. 1.14). This area is heavily involved in the synthesis of fatty acids and steroids, certain aspects of carbohydrate metabolism, and detoxification reactions of lipid soluble drugs and alcohol. In skeletal muscle, the smooth endoplasmic reticulum is a reservoir of Ca++, the release of which stimulates contraction of a muscle fiber. When chronically exposed to alcohol or barbiturates, the amount of smooth endoplasmic reticulum in a cell increases substantially. Expansion of the smooth endoplasmic reticulum is a major contributor to the tolerance of high concentrations of these substances seen in chronic