The basic unit of a living organism is the cell. In humans, each tissue is composed of a variety of cell types, which mostly differ from those cell types in other tissues. The diversity of cell types dictates the function of the tissue and organs in which they reside, and each cell type has unique structural features that reflect its role. In spite of their diversity in structure, human cell types have certain architectural features in common, such as the plasma membrane, membranes around the nucleus and organelles, and a cytoskeleton (Fig. 10.1). In this chapter, we review common features of cell structure, the functions of organelles, the transport systems for compounds into cells and between organelles, and signaling by chemical messengers.

Plasma membrane. The cell membrane consists of a lipid bilayer that serves as a selective barrier; it restricts the entry and exit of compounds. Within the plasma membrane, different integral membrane proteins facilitate the transport of compounds by energy-requiring active transport, facilitated diffusion, or by forming pores or gated channels. The plasma membrane is supported by a membrane skeleton composed of proteins.

Organelles and Cytoplasmic Membrane Systems. Most organelles within the cell are compartments surrounded by a membrane system that restricts exchange of compounds and information with other compartments (see Fig. 10.1). In general, each organelle has unique functions that are served by the enzymes and other compounds it contains. Lysosomes contain hydrolytic enzymes that degrade proteins and other large molecules. The nucleus contains the genetic material and carries out DNA replication and transcription of DNA. The transcription of DNA generates mRNA, which binds to ribosomes in the cytosol to initiate protein synthesis. For certain proteins, the ribosomes become attached to a complex membrane system called the endoplasmic reticulum; for other proteins, synthesis is completed on ribosomes that remain in the cytoplasm. The endoplasmic reticulum is also involved in lipid synthesis and transport of molecules to the Golgi. The Golgi forms vesicles for transport of molecules to the plasma membrane and other membrane systems, and for secretion. Mitochondria are organelles committed to fuel oxidation and ATP generation. Peroxisomes contain many enzymes that use or produce hydrogen peroxide. The cytosol is the intracellular compartment free of organelles and membrane systems.

Chemical Messengers. Chemical messengers (also called signaling molecules) transmit messages between cells. They are secreted from one cell in response to a specific stimulus and travel to a target cell, where they bind to a specific receptor and elicit a response (Fig. 10.2). In the nervous system, these chemical messengers are called neurotransmitters; in the endocrine system, they are called hormones; and in the immune system, they are called cytokines. Additional chemical messengers include retinoids, eicosanoids, and growth factors. Depending on the distance between the secreting and target cells, chemical messengers can be classified as endocrine (travel in the blood), paracrine (travel between nearby cells), juxtacrine (cell–cell contact-dependent signaling), or autocrine (act on the same cell that produces the message).

Receptors and Signal Transduction. Receptors are proteins that contain a binding site specific for a chemical messenger and an effector site involved in transmitting the message (see Fig. 10.2). The effector site may interact with another protein or with DNA. They may be either plasma membrane receptors (which span the plasma membrane and contain an extracellular binding domain for the messenger) or intracellular binding proteins (for messengers able to diffuse into the cell) (see Fig. 10.2). Most plasma membrane receptors fall into the categories of ion-channel receptors, tyrosine kinase receptors, tyrosine kinase–associated receptors, serine–threonine kinase receptors, or G-protein coupled (heptahelical) receptors (proteins with seven α-helices spanning the membrane). When a chemical messenger binds to a receptor, the signal it is carrying must be converted into an intracellular response. This conversion is called signal transduction.

Signal Transduction for Intracellular Receptors. Most intracellular receptors are gene–specific transcription factors, proteins that bind to DNA and regulate the transcription of certain genes. (Gene transcription is the process of copying the genetic code from DNA to RNA and is discussed further in Chapter 13.)

Signal Transduction for Plasma Membrane Receptors. Mechanisms of signal transduction that follow the binding of signaling molecules to plasma membrane receptors include phosphorylation of receptors at tyrosine residues (receptor tyrosine kinase activity), conformational changes in signal transducer proteins (e.g., proteins with SH2 domains, the monomeric G-proteins like Ras, or heterotrimeric G-proteins), or increases in the levels of intracellular second messengers. Second messengers are nonprotein molecules that are generated inside the cell in response to hormone binding and that continue transmission of the message. Examples include 3′,5′-cyclic AMP (cAMP), inositol trisphosphate (IP₃), and diacylglycerol (DAG).

Signaling often requires a rapid response and rapid termination of the message, which may be achieved by internalization of the receptor, by degradation of the receptor itself, by degradation of the messenger or second messenger, the conversion of GTP to GDP on GTP-dependent signaling molecules, deactivation of signal transduction kinases by phosphatases, or other means.

THE WAITING ROOM

Al M. had been drinking heavily when he drove his car off the road and was taken to the hospital emergency department (see Chapters 8 and 9). Although he suffered only minor injuries, his driving license was suspended.

Two years after Dennis V. recovered from his malathion poisoning, he visited his grandfather, Percy V. took Dennis V. with him to a picnic at the shore, where they ate steamed crabs. Early the next morning, Dennis V. experienced episodes of profuse watery diarrhea and vomiting. Percy V. rushed him to the hospital emergency department. Dennis V.’s hands and feet were cold, he appeared severely dehydrated, and he was approaching hypovolemic shock (a severe drop in blood pressure). He was diagnosed with cholera, caused by the bacteria Vibrio cholerae. Dennis V. was placed on intravenous rehydration therapy, followed by oral rehydration therapy with high glucose and sodium (Na⁺) containing fluids and given antibiotics. In his intestinal mucosal cells, the cholera toxin A subunit indirectly activated the cystic fibrosis transmembrane conductance regulator (CFTR) channel, resulting in the secretion of chloride and sodium ions into his intestinal lumen. Ion secretion was followed by loss of water, resulting in vomiting and watery diarrhea.

Before Lotta T. was treated with allopurinol for prevention of a gouty attack (see Chapter 8), her physician-administered colchicine (acetyl trimethyl colchicinic acid) for the acute attack of gout affecting her great toe. After taking two doses of colchicine divided over 1 hour (1.2 mg for the first dose, followed 1 hour later by 0.6 mg), the throbbing pain in her toe had abated significantly. The redness and swelling also seemed to have lessened slightly.

Mia S. is a 37-year-old woman who complains of increasing muscle fatigue, which she notices mostly with eating: halfway through a meal she has trouble chewing her food. If she rests for five to ten minutes, her strength returns to normal. She also notes that if she talks on the phone, her ability to form words gradually decreases because of fatigue of the muscles of speech. She also reports that by evening, her upper eyelids droop to the point that she has to pull her upper lids back to see normally. These symptoms are becoming increasingly severe. When she is asked to sustain an upward gaze, her upper eyelids eventually drift downward involuntarily. When she is asked to hold both arms straight out in front of her for as long as she is able, both arms begin to drift downward within minutes. Her physician suspects that Mia S. has myasthenia gravis and orders a test to determine whether she has antibodies in her blood directed against the acetylcholine receptor.

Ann R., who suffers from anorexia nervosa, has increased her weight from 85 to 102 lb (see Chapter 9). On the advice of her physician, she has been eating more to prevent fatigue during her daily jogging regimen. She runs about 10 miles before breakfast every other day and forces herself to drink a high-energy supplement immediately afterward.

I. Compartmentation in Cells

The structure of a typical eukaryotic cell is shown in Figure 10.1. The cells of humans and other animals are classified as eukaryotes because the genetic material is organized into a membrane-enclosed nucleus. In contrast, bacteria are classified as prokaryotes, as they do not contain a compartmentalized nucleus or other organelles typically found in eukaryotic cells.

Membranes are lipid-containing structures that separate the contents of the compartment they surround from its environment. An outer plasma membrane separates the cell from the external environment. Organelles (such as the nucleus, mitochondria, lysosomes, and peroxisomes) are also surrounded by membrane systems that separate the internal compartment of the organelle from the intracellular milieu, known as the cytosol. The function of these membranes is to allow the organelle to collect or concentrate enzymes and other molecules serving a common function into a compartment within a localized environment. The transporters and receptors in each membrane system control this localized environment and facilitate communication of the cell or organelle with the surrounding milieu.

The following sections describe the various organelles and membrane systems found in most human cells and outline the relationship between their properties and function. Not all cells in the human are alike. Different cell types differ qualitatively or quantitatively in their organelle content, and their organelles may contain vastly different amounts of a particular enzyme, consistent with the function of the cell. For example, liver mitochondria contain a key enzyme for synthesizing ketone bodies, but they lack a key enzyme required for their use. The reverse is true in muscle mitochondria. Thus, the enzyme content of the organelles varies somewhat from cell type to cell type.

All mammalian cells are enclosed by a plasma membrane composed of a lipid bilayer (two layers) containing embedded proteins (Fig. 10.3). The membrane layer facing the “inside” of the organelle or cell is termed the inner leaflet; the other layer is the outer, or external, leaflet. The membranes are continuous and sealed so that the hydrophobic lipid bilayer selectively restricts the exchange of polar compounds between the external fluid and the intracellular compartment. The membrane is referred to as a fluid mosaic because it consists of a mosaic of proteins and lipid molecules that can for the most part move laterally in the plane of the membrane. The proteins are classified as integral proteins, which span the cell membrane, or peripheral proteins, which are attached to the membrane surface through electrostatic bonds to lipids or integral proteins. Many of the proteins and lipids on the external leaflet of the plasma membrane contain covalently bound carbohydrate chains and therefore are called glycoproteins and glycolipids. This layer of carbohydrate on the outer surface of the cell is called the glycocalyx. The variable carbohydrate components of the glycolipids on the cell surface function, in part, as cell recognition markers for small molecules or other cells.

1. Lipids in the Plasma Membrane

Each layer of the plasma membrane lipid bilayer is formed primarily by phospholipids, which are arranged with their hydrophilic head groups facing the aqueous medium and their fatty acyl tails forming a hydrophobic membrane core (see Fig. 10.3). The principal phospholipids in the membrane are the glycerol lipids phosphatidylcholine (also named lecithin), phosphatidylethanolamine, and phosphatidylserine, and the sphingolipid sphingomyelin (the structure of the phospholipids can be seen in Chapters 5 and 31). Sphingosine also forms the base for the glycosphingolipids, which are membrane-anchored lipids with carbohydrates attached. The lipid composition varies among different cell types, with phosphatidylcholine being the major plasma membrane phospholipid in most cell types and glycosphingolipids the most variable.

The lipid composition of the bilayer is asymmetrical, with a higher content of phosphatidylcholine and sphingomyelin in the outer leaflet and a higher content of phosphatidylserine and phosphatidylethanolamine in the inner leaflet. Phosphatidylinositol, which can also function in the transfer of information from hormones and neurotransmitters across the cell membrane (see Section XII.C.3 of this chapter), is also primarily found in the inner leaflet. Phosphatidylserine contains a net negative charge that contributes to the membrane potential and may be important for binding positively charged molecules within the cell.

Cholesterol, which is interspersed between the phospholipids, maintains membrane fluidity. The presence of cholesterol and the cis unsaturated fatty acids in the membrane prevent the hydrophobic chains from packing too closely together. As a consequence, lipid and protein molecules that are not bound to external or internal structural proteins can rotate and move laterally in the plane of the leaflet. This movement enables the plasma membrane to partition between daughter cells during cell division, to reorganize as cells pass through capillaries, and to form and fuse with vesicle membranes. Cholesterol can also stabilize very fluid membranes by increasing interactions between the fatty acids of phospholipids through hydrophobic interactions with the cholesterol ring structure. The fluidity of the membrane is also partially determined by the unsaturated fatty acid content in the membrane lipids.

2. Proteins in the Plasma Membrane

Integral proteins contain transmembrane domains with hydrophobic amino acid side chains that interact with the hydrophobic portions of the lipids to seal the membrane (see Fig. 10.3). Hydrophilic regions of the proteins protrude into the aqueous medium on both sides of the membrane. Many of these proteins function as either channels or transporters for the movement of compounds across the membrane, as receptors for the binding of hormones and neurotransmitters, or as structural proteins (Fig. 10.4).

Peripheral membrane proteins, which were originally defined as those proteins that can be released from the membrane by ionic solvents, are bound through weak electrostatic interactions with the polar head groups of lipids or with integral proteins. One of the best-characterized classes of peripheral proteins is the spectrin family of proteins, which are bound to the intracellular membrane surface and provide mechanical support for the membrane. Spectrin is bound to actin, which together forms a structure that is called the inner membrane skeleton or the cortical skeleton (see Fig. 10.4).

A third classification of membrane proteins consists of lipid-anchored proteins bound to the inner or outer surface of the membrane. The glycophosphatidylinositol glycan (GPI) anchor is a covalently attached lipid that anchors proteins to the external surface of the membrane (Fig. 10.5). Several proteins involved in hormonal regulation are anchored to the internal surface of the membrane through palmityl (C16) or myristyl (C14) fatty acyl groups or through geranylgeranyl (C20) or farnesyl (C15) isoprenyl groups (see Fig. 6.12). However, many integral proteins also contain attached lipid groups to increase their stability in the membrane.

B. Transport of Molecules across the Plasma Membrane

Membranes form hydrophobic barriers around cells to control the internal environment by restricting the entry and exit of molecules. As a consequence, cells require transport systems to permit the entry of small polar compounds or ions that they need (e.g., glucose) to concentrate inside the cell (e.g., K⁺) and to expel other compounds (e.g., Ca²⁺ and Na⁺). The transport systems for small organic molecules and inorganic ions generally fall into four categories: first is simple diffusion through the lipid bilayer (examples include gases such as oxygen and carbon dioxide, and lipid-soluble substances, such as steroid hormones); second is facilitative diffusion (many sugars are transported by facilitative diffusion); third is gated channels (transmembrane proteins form a pore for ions that is either opened or closed in response to a stimulus, whether it be voltage changes across the membrane, the binding of a compound, or a regulatory change in the intracellular domain); and fourth is active transport pumps (energy, usually in the form of ATP hydrolysis, is used to allow compounds to move against their concentration gradient) (Fig. 10.6). These transport mechanisms are classified as passive if energy is not required, or active if energy is required. Primary active transport occurs when a gradient is established across the membrane, using energy. The Na⁺, K⁺-ATPase creates both sodium and potassium gradients across the membrane, by transporting three sodium ions out of the cell in exchange for two potassium ions entering the cell, powered by the hydrolysis of ATP. The creation of the sodium gradient (the sodium concentration outside the cell is much greater than the sodium concentration inside the cell) leads to secondary active transport of glucose and amino acids. The transporters for these compounds bind sodium and the co substrate (either glucose or an amino acid), and then using the sodium gradient as a driving force, transports both the sodium and the co substrate into the cell. Thus, glucose and amino acids are concentrated within cells via the creation of the sodium gradient by the Na⁺, K⁺-ATPase.

In addition to these mechanisms for the transport of small individual molecules, cells use a process named endocytosis. The plasma membrane extends or invaginates to surround a particle, a foreign cell, a membrane receptor, or extracellular fluid, which then closes into a vesicle that is released into the cytoplasm (see Fig. 10.6). Receptor-mediated endocytosis can occur in either of two ways. The first is the formation of clathrin-coated vesicles that mediate the internalization of membrane-bound receptors in vesicles coated on the intracellular side with subunits of the protein clathrin. Cholesterol uptake, as mediated by the low-density lipoprotein (LDL) receptor, occurs via this mechanism. The second is caveolar endocytosis, in which caveolae (small invaginations of the plasma membrane) oligomerize and form endocytotic vesicles containing a receptor. Insulin uptake in fat cells occurs via this mechanism. Potocytosis is the name given to endocytosis that occurs via caveolae (small invaginations or “caves”), which are regions of the cell membrane with a unique lipid and protein composition (including the protein caveolin-1). The transport of the vitamin folate occurs via potocytosis.

III. Lysosomes

Lysosomes are the intracellular organelles of digestion and are enclosed by a single membrane that prevents the release of its digestive enzymes into the cytosol. They are central to a wide variety of bodily functions that involve the elimination of unwanted material and recycling of their components, including the destruction of infectious bacteria and yeast, recovery from injury, tissue remodeling, involution of tissues during development, and normal turnover of cells and organelles. The lysosomal digestive enzymes include nucleases, phosphatases, glycosidases, esterases, and proteases (Fig. 10.7). These enzymes are all hydrolases, enzymes that cleave amide, ester, and other bonds through the addition of water. Many of the products of lysosomal digestion, such as amino acids, return to the cytosol. Lysosomes are therefore involved in recycling compounds. The proteases are classified as serine, cysteine, or aspartyl proteases, depending on the amino acid residue at the active site of the enzyme involved in the hydrolytic reaction. The cysteine proteases are also known as cathepsins. Most of these lysosomal hydrolases have their highest activity near a pH of approximately 5.5 (the optimal pH for hydrolysis). The intralysosomal pH is maintained near 5.5 principally by v-ATPases (vesicular ATPases), which actively pump protons into the lysosome at the expense of ATP hydrolysis. The cytosol and other cellular compartments have a pH nearer to 7.2 and are therefore protected from escaped lysosomal hydrolases.

IV. Mitochondria

Mitochondria contain most of the enzymes for the pathways of fuel oxidation and oxidative phosphorylation and thus generate most of the ATP required by mammalian cells. Each mitochondrion is surrounded by two membranes, a mostly impermeable outer membrane and a highly impermeable inner membrane, separating the mitochondrial matrix from the intermembrane space (Fig. 10.8). The inner membrane forms invaginations known as cristae containing the electron transport chain and ATP synthase. Most of the enzymes for the Krebs tricarboxylic acid (TCA) cycle and other pathways for oxidation are located in the mitochondrial matrix, the compartment enclosed by the inner mitochondrial membrane. (The TCA cycle and the electron transport chain are described in more detail in Chapters 23 and 24.)

The inner mitochondrial membrane is highly impermeable, and the proton gradient that is built up across this membrane during oxidative phosphorylation is essential for ATP generation from adenosine diphosphate (ADP) and phosphate. The transport of ions and other small molecules across the inner mitochondrial membrane occurs principally through facilitative transporters in a type of secondary active transport powered by a proton gradient established by the electron transport chain. The outer membrane contains pores made from proteins called porins and is permeable to molecules with a molecular weight of up to about 1,000 Da.

The largest of the subcellular organelles of animal cells is the nucleus (Fig. 10.9). Most of the genetic material of the cell is located within the chromosomes in the nucleus, which are composed of DNA, an equal weight of small, positively charged proteins called histones, and a variable amount of other proteins. These nucleoprotein complexes comprise what is called chromatin. The nucleolus, a substructure of the nucleus, is the site of ribosomal RNA (rRNA) transcription and processing, and of ribosome assembly. Ribosomes are required for the synthesis of proteins. Replication, transcription, translation, and the regulation of these processes are the major focus of the molecular biology section of this text (see Section III).

The nucleus is separated from the rest of the cell (the cytoplasm) by the nuclear envelope, which consists of two membranes joined at nuclear pores. The outer nuclear membrane is continuous with the rough endoplasmic reticulum. Transport through the pores is bidirectional. An example of such transport is the initial phase of protein synthesis. To convert the genetic code of the DNA into the primary sequence of a protein, DNA is transcribed into RNA, which is spliced and modified into mRNA. The mRNA travels through the nuclear pores into the cytoplasm, where it is translated into the primary sequence of a protein on ribosomes. Ribosomes, which are generated in the nucleolus, also must travel through nuclear pores to the cytoplasm. Conversely, proteins required for replication, transcription, and other processes enter into the nucleus through these pores. Proteins contain specific sequences of amino acids known as a nuclear localization signal (NLS) or nuclear export signal (NES) that dictate whether a protein may move out of or into the nucleus. Thus, the direction of transport through the pore is specific for the molecule or complex being transported across the membrane.

The endoplasmic reticulum (ER) is a network of membranous tubules within the cell consisting of smooth endoplasmic reticulum (SER), which lacks ribosomes, and rough endoplasmic reticulum (RER), which is studded with ribosomes (Fig. 10.10). The SER has a number of functions. It contains enzymes for the synthesis of many lipids, such as triacylglycerols and phospholipids. It also contains the cytochrome P450 oxidative enzymes involved in the metabolism of drugs and toxic chemicals like ethanol and the synthesis of hydrophobic molecules like steroid hormones. Glycogen is stored in regions of liver cells that are rich in SER.

The RER is involved in the synthesis of proteins, which are targeted to the plasma membrane, for secretion, or to another intracellular organelle. Ribosomes attached to the membranes of the RER give them their “rough” appearance. Proteins produced on these ribosomes enter the lumen of the RER, travel to another membrane system (the Golgi complex) in vesicles, and are subsequently either secreted from the cell, sequestered within membrane-enclosed organelles such as lysosomes, or embedded in the plasma membrane. Posttranslational modifications of these proteins, such as the initiation of N-linked glycosylation and the addition of lipid-based anchors, and disulfide formation, occur in the RER. In contrast, proteins encoded by the nucleus and found in the cytoplasm, peroxisomes, or mitochondria are synthesized on free ribosomes in the cytosol and are seldom modified by the attachment of oligosaccharides.

Stay updated, free articles. Join our Telegram channel

Join