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Cell Membranes and Signaling If you are like most people, you consume a significant amount of caffeine every day. In fact, more than 90 percent of North Americans and Europeans drink coffee or tea to get their “caffeine fix.” Coffee and tea plants contain caffeine as a defense against the insects that eat them. Caffeine acts as an insecticide in plant parts that are particularly vulnerable to insect attacks, such as seeds, young seedlings, and leaves. But it is not toxic to humans. Legend has it that about 5,000 years ago, a Chinese emperor found out by accident that a pleasant beverage could be made by boiling tea leaves. About 1,000 years ago, monks living in what is now Ethiopia found that roasting coffee seeds (“beans”) gave a similarly pleasant effect and that the beverage kept them awake during long periods of prayer. Caffeine is now the most widely consumed psychoactive molecule in the world, but unlike other psychoactive drugs, it is not subject to government regulation. Most people know from personal experience what caffeine does to the body: because it keeps us awake, it obviously affects the brain. In fact, it is often given to premature babies in the hospital nursery when they stop breathing. But it also affects other parts of the body—for example, it increases urination and speeds up the heart. How does this molecule work? The key to understanding caffeine’s action is to understand how it interacts with the cell membrane. In Chapter 4 we introduce the concept of the membrane as a structural boundary between the inside of a cell and the surrounding environment. The plasma membrane physically separates the cell cytoplasm from its
surroundings and helps maintain chemical differences between these two environments. The same can be said of the membranes that surround cell organelles, separating them from the cytoplasmic environment. When caffeine arrives at a cell in the body, it first encounters the plasma membrane. The properties of this membrane determine whether and how the cell will react to caffeine. Will it cross the membrane boundary and enter the cell? What determines whether it crosses the membrane? If it does not, how can caffeine’s interactions with membrane components lead to changes in cell function?
What role does the cell membrane play in the body’s response to caffeine?
Many people rely on caffeine to wake themselves up and to keep their minds alert.
KEY ConCEpTS 5.1 Biological Membranes Have a Common Structure and Are Fluid 5.2 Some Substances Can Cross the Membrane by Diffusion 5.3 Some Substances Require Energy to Cross the Membrane 5.4 Large Molecules Cross the Membrane via Vesicles 5.5 The Membrane Plays a Key Role in a Cell’s Response to Environmental Signals 5.6 Signal Transduction Allows the Cell to Respond to Its Environment
62 Chapter 5 | Cell Membranes and Signaling
Outside of cell
Carbohydrates are attached to the outer surface of proteins (forming glycoproteins) or lipids (forming glycolipids).
In animal cells, some membrane proteins associate with filaments in the extracellular matrix.
Peripheral membrane proteins do not penetrate the bilayer at all.
Cholesterol molecules interspersed among phospholipid tails in the bilayer influence the fluidity of fatty acids in the membrane.
Biological Membranes Have a Common Structure and Are Fluid
The evolution of cellular life required the presence of a boundary, a need fulfilled by biological membranes. Like much of nature at the cellular level, there is a common molecular structure that has evolved to perform membrane functions. This structure and its functions are determined by the constituents of biological membranes: lipids, proteins, and carbohydrates. An important concept that emerges from our consideration of these molecules is polarity and how polarity influences the way a molecule interacts with water. The nonpolar regions of phospholipids and membrane proteins interact to form an insoluble barrier. The phospholipid bilayer serves as a lipid “lake” in which a variety of proteins “float” (FIGURE 5.1). This general design is known as the fluid mosaic model. Membranes contain a wide array of proteins, some of which arePOL noncovalently embedded in the phospholipid bilayer. These Hillis proteins are held within the membrane by their hydrophobic Sinauer Associates Morales regions, orStudio domains, while the proteins’ hydrophilic domains are Figure 05.01 Date 06-28-10 exposed to the watery conditions on one or both sides of the bilayer. Membrane proteins have several functions: they move materials through the membrane and receive chemical signals from the cell’s external environment. The carbohydrates associated with membranes are attached to either lipids or protein molecules. They are generally located on the outside of the cell, where they interact with substances in the external environment. Like some membrane proteins, carbohydrates are crucial for recognizing specific molecules, such as those on the surfaces of adjacent cells (see Chapter 4).
Some membrane proteins interact with the interior cytoskeleton.
Some integral proteins cross the entire phospholipid bilayer; others penetrate only partially into the bilayer.
FIGURE 5.1 Membrane Molecular Structure The general molecular structure of biological membranes is a continuous phospholipid bilayer in which proteins are embedded. The phospholipid bilayer separates two aqueous regions, the external environment outside the cell and the cell cytoplasm.
yourBioPortal.com Go to WEB ACTIVITY 5.1 Membrane Molecular Structure
Each membrane is made up of constituents that are suitable for the specialized functions of the cell or organelle it surrounds. As you read about the different molecules in membranes, keep in mind that some membranes contain many protein molecules, others are lipid-rich, others have significant amounts of cholesterol or other sterols, and still others are rich in carbohydrates.
Lipids form the hydrophobic core of the membrane The lipids in biological membranes are usually phospholipids. Recall that some compounds are hydrophilic (“water-loving”) and others are hydrophobic (“water-hating”), and that a phospholipid molecule has regions of both kinds: • Hydrophilic regions. The phosphorus-containing “head” of a phospholipid is electrically charged and therefore associates with polar water molecules. • Hydrophobic regions. The long, nonpolar fatty acid “tails” of a phospholipid associate with other nonpolar materials, but they do not dissolve in water or associate with hydrophilic substances.
5.2 5.1 Biological Membranes Have a Common Structure and Are Fluid 63 Because of these properties, one way in which phospholipids can coexist with water is to form a bilayer, with the fatty acid “tails” of the two layers interacting with each other, and the polar “heads” facing the outside, aqueous environment:
LINK Review the properties of phospholipid bilayers in Concept 2.4 (pp. 32–33) The thickness of a biological membrane is about 8 nm (0.008 µm), which is twice the length of a typical phospholipid. This thickness is about 8,000 times thinner than the page you are reading. As we note in Chapter 4, in the laboratory it is possible to make artificial bilayers with the same organization as natural membranes. Small holes in such bilayers seal themselves spontaneously. The capacity of phospholipids to associate with one another and maintain a bilayer organization helps biological membranes fuse during vesicle formation, phagocytosis, and related processes (see Chapter 4). Although biological membranes all share a similar structure, there are many different kinds of phospholipids, and membranes from different cells or organelles may differ greatly in their lipid composition. Not only do membranes contain many different kinds of phospholipids, but also a significant proportion of the lipid content in an animal cell membrane may be cholesterol. Phospholipids can differ in terms of fatty acid chain length (number of carbon atoms), degree of unsaturation (number of double bonds) in the fatty acids, and the kinds of polar (phosphate-containing) groups present. The most common fatty acids in membranes have chains with 16–18 carbon atoms and 0–2 double bonds. Saturated fatty acid chains (those with no double
bonds) allow close packing of phospholipids in the bilayer, whereas the “kinks” in the unsaturated fatty acids (see Figure 2.12) make for a less dense, more fluid packing. Up to 25 percent of the lipid content of an animal cell plasma membrane may be cholesterol. When present, cholesterol is important for membrane integrity; the cholesterol in your membranes is not hazardous to your health. A molecule of cholesterol is usually situated next to an unsaturated fatty acid. The fatty acids of the phospholipids make the membrane somewhat fluid—about as fluid as lightweight machine oil. This fluidity permits some molecules to move laterally within the plane of the membrane. A given phospholipid molecule in the plasma membrane can travel from one end of the cell to the other in a little more than one second! However, it is rare for a phospholipid molecule in one half of the bilayer to spontaneously flip over to the other side. For that to happen, the polar part of the molecule would have to move through the hydrophobic interior of the membrane. Since spontaneous flip-flops are rare, the inner and outer halves of the bilayer may be quite different in the kinds of phospholipids they contain. Membrane fluidity is affected by several factors, two of which are particularly important: • Lipid composition. Cholesterol and long-chain, saturated fatty acids pack tightly together, resulting in less fluid membranes. Unsaturated fatty acids or those with shorter chains tend to increase membrane fluidity. Some anesthetics are nonpolar and act by inserting into the membrane, where they reduce the fluidity of nerve cell membranes, and thereby decrease nerve activity. • Temperature. Membrane fluidity declines under cold conditions because molecules move more slowly at lower temperatures. For example, when your fingers get numb after contact with ice, it is due to a reduction in membrane fluidity in nerve cells. To address this problem, some organisms simply change the lipid composition of their membranes when their environment gets cold, replacing saturated with unsaturated fatty acids and using fatty acids with shorter chains. These changes play a role in the survival of plants, bacteria, and hibernating animals during the winter.
Apply the Concept POL Hillis Membranes Have a Common Structure and Are Fluid Biological Sinauer Associates
Morales Studio lipids of a cell can be labeled with a fluorescent The membrane Figure INTXT05.01 Date tag so the entire surface of06-15-10 the cell will glow evenly under ultraviolet light. If a strong laser light is then shone on a tiny region of the cell, that region gets bleached (the strong light destroys the fluorescent tag) and there is a “hole” in the cell surface fluorescence. After the laser is turned off, the hole gradually fills in with fluorescent lipids that diffuse in from other parts of the membrane. The time it takes for the hole to disappear is a measure of membrane fluidity. The table shows some data for cells with altered membrane compositions. Explain the effect of each alteration.
Time (sec) for “hole” to Condition become fluorescent
Decreased length of fatty acid chains
Increased unsaturation of fatty acid chains
Increased membrane protein content
64 Chapter 5 | Cell Membranes and Signaling
yourBioPortal.com Go to INTERACTIVE TUTORIAL 5.1 Lipid Bilayer: Temperature Effects on Composition
Membrane proteins are asymmetrically distributed All biological membranes contain proteins. Typically, plasma membranes have about 1 protein molecule for every 25 phospholipid molecules. This ratio varies depending on membrane function. In the inner membrane of the mitochondrion, which is specialized for energy processing, there is 1 protein for every 5 lipids. By contrast, myelin—a membrane that encloses portions of some neurons (nerve cells) and acts as an electrical insulator— has only 1 protein for every 70 lipids. Recall from Table 3.2 that some amino acids contain nonpolar, hydrophobic R groups, while others contain polar (charged), hydrophilic R groups. The arrangement of these amino acids in a membrane protein determines whether the membrane protein will insert into the nonpolar lipid bilayer and how it will be positioned: Hydrophilic R groups (side chains) in exposed parts of the protein interact with aqueous environments.
Outside of cell (aqueous)
Hydrophobic interior of bilayer
Hydrophobic R groups interact with the hydrophobic core of the membrane away from water.
Inside of cell (aqueous)
There are two general types of membrane proteins: • Peripheral membrane proteins lack exposed hydrophobic groups and are not embedded in the bilayer. Instead, they have polar or charged regions that interact with exposed parts of integral membrane proteins, or with the polar heads of phospholipid molecules (see Figure 5.1). • Integral membrane proteins are at least partly embedded in the phospholipid bilayer (see Figure 5.1). Like phospholipids, these proteins have both hydrophilic and hydrophobic regions. Membrane proteins and lipids generally interact only noncovalently. The polar ends of proteins can interact with the polar ends of lipids, and the nonpolar regions of both molecules can interact hydrophobically. However, some membrane proteins have fatty acids or other lipid groups covalently attached to them. Proteins in this subgroup of integral membrane proteins are referred to as anchored membrane proteins, because it is their hydrophobic lipid components that anchor them in the phospholipid bilayer. Proteins are asymmetrically distributed on the inner and outer surfaces of membranes. An integral membrane protein that extends all the way through the phospholipid bilayer and
protrudes on both sides is known as a transmembrane protein. In addition to one or more transmembrane domains that extend through the bilayer, such a protein may have domains with other specific functions on the inner and outer sides of the membrane. Transmembrane proteins are always oriented the same way— domains with specific functions inside or outside the cell are always found on the correct side of the membrane. Peripheral membrane proteins are localized on one side of the membrane or the other. This asymmetrical arrangement gives the two surfaces of the membrane different properties. As we will soon see, these differences have great functional significance. Like lipids, some membrane proteins move relatively freely within the phospholipid bilayer. Cell fusion experiments illustrate this migration dramatically. When two cells fuse, a single continuous membrane forms around both cells, and some proteins from each cell distribute themselves uniformly around this membrane (FIGURE 5.2). Although some proteins are free to migrate throughout the membrane, others appear to be contained within specific regions. These membrane regions are like a corral of horses on a farm: the horses are free to move around within the fenced area but not outside it. For example, a muscle cell protein that recognizes a chemical signal from a neuron is normally found only within a specific region of the plasma membrane, where the neuron meets the muscle cell. How does this happen? Proteins inside the cell can restrict the movement of proteins within a membrane. Components of the cytoskeleton may be attached to membrane proteins protruding into the cytoplasm (see Figure 5.1). The stability of the cytoskeleton may thus restrict the movement of attached membrane proteins.
Plasma membrane carbohydrates are recognition sites In addition to lipids and proteins, the plasma membrane contains carbohydrates. The carbohydrates are located on the outer surface of the plasma membrane and serve as recognition sites for other cells and molecules. Membrane-associated carbohydrates may be covalently bonded to lipids or to proteins: • A glycolipid consists of a carbohydrate covalently bonded to a lipid. Extending outside the cell surface, the carbohydrate may serve as a recognition signal for interactions between cells. For example, the carbohydrates on some glycolipids change when cells become cancerous. This change may allow white blood cells to target cancer cells for destruction. • A glycoprotein consists of a carbohydrate covalently bonded to a protein. The bound carbohydrate is an oligosaccharide of 15 or fewer monosaccharide units (see Concept 2.3). These oligosaccharides often function as signaling sites, as do the carbohydrates attached to glycolipids. The “alphabet” of monosaccharides on the outer surfaces of membranes can generate a large diversity of messages. There may be linear or branched oligosaccharides with many different three-dimensional shapes. An oligosaccharide of a specific shape on one cell can bind to a complementary shape on an adjacent cell. This binding is the basis of cell–cell adhesion:
5.2 5.1 Biological Membranes Have a Common Structure and Are Fluid 65 Cells
INVESTIGATION Exposed regions of membrane glycoproteins bind to each other, causing cells to adhere.
FIGURE 5.2 Rapid Diffusion of Membrane Proteins A human cell can be fused to a mouse cell in the laboratory, forming a single large cell (heterokaryon). This phenomenon was used to test whether membrane proteins can diffuse independently in the plane of the plasma membrane. HYPOTHESIS Proteins embedded in a membrane can diffuse freely within the membrane. METHOD
FRONTIERS As an animal embryo develops, cells detach from one region, move, and then reattach at another region. This requires that cell membrane glycoproteins with binding specificities for adjacent cells are replaced by new ones with different specificities, so the cells can bind to their new neighbors. To investigate embyonic development, scientists are making genetically modified organisms whose embryonic cell membranes lack one or another surface binding component.
The mouse cell has a membrane protein that can be labeled with a green dye.
The human cell has a membrane protein that can be labeled with a red dye.
1 The cells are fused together to create a heterokaryon.
Membranes are constantly changing Membranes in eukaryotic cells are constantly forming, transforming from one type to another, fusing with one another, and breaking down. As we discuss in Chapter 4, fragments of membrane move (in the form of vesicles) from the endoplasmic reticulum (ER) to the Golgi apparatus, and from the Golgi apparatus to the plasma membrane (see Figure 4.7). Secondary lysosomes form when primary lysosomes from the Golgi apparatus fuse with phagosomes from the plasma membrane (see Figure 4.8). Because all membranes have a similar appearance under the electron microscope, and because they interconvert readily, we might expect all subcellular membranes to be chemically identical. However, that is not the case, for there are major chemical differences among the membranes of even a single cell. Membranes are chemically when they form parts of certain organPOLchanged Hillis Sinauer elles. InAssociates the Golgi apparatus, for example, the membranes of Morales Studio the cis face closely resemble those of the endoplasmic reticulum Figure INTXT05.03 Date 06-15-10 in chemical composition, but those of the trans face are more similar to the plasma membrane.
Do You Understand Concept 5.1? • What are the differences between peripheral and in-
2 Initially, the mouse and
human membrane proteins are on different sides of the heterokaryon.
3 After 40 minutes, the mouse and human membrane proteins are intermixed.
CONCLUSION Membrane proteins can diffuse rapidly in the plane of the membrane. ANALYZE THE DATA The experiment was repeated at various temperatures with the following results:
tegral membrane proteins?
• Why do phospholipids shaken in a water environment
0 15 20 26
assemble into vesicles surrounded by a lipid bilayer?
• What is the evidence for membrane fluidity? • If cells that recognize and attach to one another are
separated and then shaken in a liquid medium, they re-aggregate because of binding between their membrane glycoproteins. What would happen if the re-aggregation experiment were conducted after the cells are treated to remove cell surface carbohydrates?
Cells with mixed proteins (%) 0 8 42 77
Plot these data on a graph of Percentage Mixed vs. Temperature. Explain these data, relating the results to the concepts of diffusion and membrane fluidity.
Go to yourBioPortal.com for original citations, discussions, and relevant links for all INVESTIGATION figures. POL Hillis Sinauer Associates Morales Studio
66 Chapter 5 | Cell Membranes and Signaling
Now that you understand the structure of biological membranes, let’s see how their components function. In the sections that follow, we will focus on the plasma membrane (the cell membrane). We’ll look at how the plasma membrane regulates the passage of substances that enter or leave a cell. Bear in mind that these principles also apply to the membranes that surround organelles. concept
Some Substances Can Cross the Membrane by Diffusion
An important property of all life is the ability to regulate the internal composition of a cell, distinguishing it from the surrounding environment. Biological membranes allow some substances, but not others, to pass through them. This characteristic of membranes is called selective permeability. There are two fundamentally different processes by which substances cross biological membranes: • The processes of passive transport do not require any input of metabolic energy to drive them. • The processes of active transport require the input of metabolic (chemical) energy from an outside source. This section focuses on passive transport across membranes. The energy for the passive transport of a substance is found in the difference between its concentration on one side of the membrane and its concentration on the other. Passive transport can occur by either of two types of diffusion: simple diffusion through the phospholipid bilayer, or facilitated diffusion through channel proteins or by means of carrier proteins.
Diffusion is the process of random movement toward a state of equilibrium In a solution, there is a tendency for all of the components to be evenly distributed. You can see this when a drop of ink is allowed to fall into a gelatin suspension (a “gel”). Initially the pigment molecules are very concentrated, but they will move about at random, slowly spreading until the intensity of color is exactly the same throughout the gel:
A solution in which the solute molecules are uniformly distributed is said to be at equilibrium. This does not mean the molecules have stopped moving; it just means they are moving in such a way that their overall distribution does not change. Diffusion is the process of random movement toward a state of equilibrium. In effect, it is a net movement from regions of greater concentration to regions of lesser concentration. Diffusion is generally a very slow process in living tissues, especially when we consider the gel-like consistency of the cell cytoplasm. For example, it would take about 3 years for a molecule of oxygen
gas (O2) to diffuse from the human lung to a cell at the fingertip! So it is not surprising that as plants and animals evolved and became larger and multicellular, those with circulatory systems to distribute vital molecules such as O2 had a distinct advantage over organisms relying on simple diffusion. How fast a substance diffuses depends on three factors: • The diameter of the molecules or ions: smaller molecules diffuse faster. • The temperature of the solution: higher temperatures lead to faster diffusion because the heat provides more energy for movement. • The concentration gradient in the system—that is, the change in solute concentration with distance in a given direction. The greater the concentration gradient, the more rapidly a substance diffuses. What does this mean for a cell surrounded by a membrane? The cytoplasm is largely a water-based (aqueous) solution, and so is the surrounding environment. In a complex solution (one with many different solutes), the diffusion of each solute depends only on its own concentration, not the concentrations of other solutes. So one might expect a substance with a higher concentration inside the cell to diffuse out, and one with a higher concentration outside the cell to diffuse in. Indeed, this does occur for some molecules.
Simple diffusion takes place through the phospholipid bilayer Some small molecules can pass through the phospholipid bilayer of the membrane by simple diffusion. A molecule that is hydrophobic and soluble in lipids can enter the membrane readily and pass through it. The more lipid-soluble the molecule is, the more rapidly it diffuses through the lipid bilayer. In contrast, electrically charged or polar molecules, such as amino acids, sugars, ions, and water, do not pass readily through a membrane, for two reasons. First, these molecules are not very soluble in the hydrophobic interior of the bilayer. Second, charged molecules will form hydrogen bonds with water and ions in the aqueous environment on either side of the membrane. The multiplicity of these hydrogen bonds prevents the substances from moving into the hydrophobic interior of the membrane.
FRONTIERS The effectiveness of many anesthetics in reducing feeling or sensation is directly related to their membrane lipid solubility. But it is not clear exactly what happens after the drug dissolves in the membrane. Scientists are investigating this by measuring the physical properties of membrane components after an anesthetic is added. Understanding how membrane lipids and proteins are affected by anesthetics may help in designing more specific drugs with fewer side effects. Osmosis is the diffusion of water across membranes Water molecules pass through specialized channels in membranes (see below) by a diffusion process called osmosis . This process depends on the relative concentrations of water
5.2 5.2 Some Substances Can Cross the Membrane by Diffusion 67 (A) Hypertonic on the outside (concentrated solutes outside) Inside of cell
(C) Hypotonic on the outside (dilute solutes outside)
Cells take up water, swell, and burst.
FIGURE 5.3 Osmosis Can Modify the Shapes of Cells
(A) In a solution that is hypertonic to the cytoplasm of a plant or animal cell, water flows out of the cell. (B) In a solution that is isotonic with the cytoplasm, the cell maintains a consistent, characteristic shape because there is no net movement of water into or out of the cell. (C) In a solution that is hypotonic to the cytoplasm, water enters the cell. An animal cell will swell and may burst under these conditions; a plant cell will not swell too much because if its rigid cell wall.
Cell body shrinks and pulls away from the cell wall (wilting).
molecules on both sides of the membrane. In a particular solution, the higher the total solute concentration, the lower the concentration of water molecules. Consider a situation where a membrane separating two different solutions allows water, but not solutes, to pass through. The water molecules will move across the membrane toward the solution with the higher solute concentration and the lower concentration of water molecules. Here we are referring to the net movement of water. Since it is so abundant, water is constantly moving (through protein channels) across the plasma membrane, into and out of cells. But if there is a concentration difference between the two sides of the membrane, the overall movement will be greater in one LIFE Conceptsor Sadava direction the other. Sinauer Associates Three terms are used to compare the solute concentrations of Morales Studio two05.03 solutions separated Figure Date 12-27-09 by a membrane: • A hypertonic solution has a higher solute concentration than the other solution with which it is being compared (FIGURE 5.3A). • Isotonic solutions have equal solute concentrations (FIGURE 5.3B). • A hypotonic solution has a lower solute concentration than the other solution with which it is being compared (FIGURE 5.3C). The concentration of solutes in the environment determines the direction of osmosis in all animal cells. A red blood cell takes up water from a solution that is hypotonic to the cell’s contents.
Cell stiffens but generally retains its shape because cell wall is present.
If this happens, the cell bursts because its plasma membrane cannot withstand the pressure created by the water entry and the resultant swelling (see Figure 5.3C). The integrity of blood cells is absolutely dependent on the maintenance of a constant solute concentration in the surrounding blood plasma—the plasma must be isotonic to the blood cells. Regulation of the solute concentrations of body fluids is thus an important process for organisms without cell walls. In contrast to animal cells, the cells of plants, archaea, bacteria, fungi, and some protists have cell walls that limit their volumes and keep them from bursting. Cells with sturdy walls take up a limited amount of water, and in so doing they build up internal pressure against the cell wall, which prevents further water from entering. This pressure within the cell is called turgor pressure; it keeps the green parts of plants upright and is the driving force for the enlargement of plant cells. It is a normal and essential component of plant growth. If enough water leaves the cells, turgor pressure drops and the plant wilts. Turgor pressure reaches about 100 pounds per square inch (0.7 kg/cm2), which is several times greater than the pressure in automobile tires.
Diffusion may be aided by channel proteins As we saw earlier, polar or charged substances such as water, amino acids, sugars, and ions do not readily diffuse across membranes. But they can cross the hydrophobic phospholipid bilayer passively (that is, without the input of energy) in one of two ways, depending on the substance:
68 Chapter 5 | Cell Membranes and Signaling
• Channel proteins are integral membrane proteins that form channels across the membrane through which certain substances can pass. • Some substances can bind to membrane proteins called carrier proteins that speed up their diffusion through the phospholipid bilayer. Both of these processes are forms of facilitated diffusion. The substances diffuse according to their concentration gradients, but their diffusion is made easier by channel or carrier proteins. Particular channel or carrier proteins allow diffusion both into and out of a cell or organelle. In other words, they can operate in both directions. We will focus here on two examples of channel proteins and discuss carrier proteins in the next section.
ion channels The best-studied channel proteins are
1 A polar substance is more concentrated
Outside of cell
on the outside than the inside of the cell.
Stimulus molecule (ligand) 2 Binding of a stimulus molecule causes the pore to open…
Hydrophobic interior of bilayer
the ion channels. As you will see in later chapters, the Closed movement of ions across membranes is important in channel 3 …and the polar substance can many biological processes, including respiration within diffuse across the membrane. Inside of cell the mitochondria, the electrical activity of the nervous system, and the opening of the pores in leaves that allow FIGURE 5.4 A Ligand-Gated Channel Protein Opens in Response to a gas exchange with the environment. Several types of ion Stimulus The channel protein is anchored in the lipid bilayer by its outer channels have been identified, each of them specific for a coating of nonpolar (hydrophobic) amino acids. The protein changes its particular ion. All of them show the same basic structure three-dimensional shape when a stimulus molecule (ligand) binds to it, openof a hydrophilic pore that allows a particular ion to move ing a pore lined with polar amino acids. This allows hydrophilic, polar subthrough it. stances to pass through. Just as a fence may have a gate that can be opened or closed, most ion channels are gated: they can be opened or closed to ion passage. A gated channel opens when a stimulus Remarkably, the oocytes began swelling immediately after being transferred to a hypotonic solution, indicating the rapid diffucauses a change in the three-dimensional shape of the channel. sion of water into the cells (FIGURE 5.5). In some cases, this stimulus is the binding of a chemical signal, or ligand. Channels controlled in this way are called ligand-gated channels (FIGURE 5.4). In contrast, a voltage-gated channel is Carrier proteins aid diffusion by binding stimulated to open or close by a change in the voltage (electrical substances charge difference) across the membrane. Another kind of facilitated diffusion involves the actual binding of the transported substance to a membrane protein called a caraquaporins for water Water crosses membranes at a much rier protein. Carrier proteins transport polar molecules such as faster rate than would be expected if it simply diffused through sugars and amino acids. the phospholipid bilayer. One way it does this is by “hitchhiking” Glucose is the major energy source for most mammalian with some ions, such as Na+, as they pass through ion channels. cells, and they require a great deal of it. Their membranes conUp to 12 water molecules may coat an ion as it traverses a chantain a carrier protein—the glucose transporter—that facilitates nel. But there is an even faster way for water to cross membranes. glucose uptake into the cell. Binding of glucose to a specific Plants and some animal cells (such as red blood and kidney cells) three-dimensional site on one side of the transport protein have membrane channels called aquaporins. These specific chancauses the protein to change its shape and release glucose on nels allow large amounts of water to move along its concentrathe other side of the membrane (FIGURE 5.6A). Since glucose is tion gradient, as you will see when we discuss water relations in usually broken down as soon as it enters the cell, there is almost plants (see Chapter 25) and animals (see Chapter 39). always a strong concentration gradient favoring glucose entry Aquaporins were first identified by Peter Agre at Duke Uni(that is, a higher concentration outside the cell than inside). The versity, who noticed a membrane protein that was present in transporter allows glucose molecules to cross the membrane red blood cells, kidney cells, and plant cells but did not know its and enter the cell much faster than they would by simple diffufunction. A colleague suggested that it might be a water channel, sion through the bilayer. This rapid entry is necessary to ensure because these cell types show rapid diffusion of water across that the cell receives enough glucose for its energy needs. their membranes. Agre tested this idea by creating egg cells (oocytes) with the protein in their membrane. An oocyte memLIFE ConceptsTransport Sadava by carrier proteins is different from simple diffuSinauer Associates sion. In both processes, the rate of movement depends on the brane does not normally permit much diffusion of water. Agre Morales Studio concentration gradient across the membrane. However, in carinjected the oocytes with the mRNA for aquaporin; the protein Figure 05.04 Date 01-20-10 rier-mediated transport, a point is reached at which increases was produced by the cells and inserted into their membrane.
5.2 5.3 Some Substances Require Energy to Cross the Membrane 69
INVESTIGATION FIGURE 5.5 Aquaporin Increases Membrane Permeability to Water A protein was isolated from the membranes of cells in which water diffuses rapidly across the membranes. When the protein was inserted into oocytes, which do not normally have it, the water permeability of the oocytes was greatly increased. HYPOTHESIS Aquaporin increases membrane permeability to water. METHOD
in the concentration gradient are not accompanied by an increased rate of diffusion. At this point, the facilitated diffusion system is said to be saturated (FIGURE 5.6B). Because there are only a limited number of carrier protein molecules per unit of membrane area, the rate of diffusion reaches a maximum when all the carrier molecules are fully loaded with solute molecules. This situation is similar to that of enzyme saturation (see Concept 3.3).
Go to ANIMATED TUTORIAL 5.1 Passive Transport
Do You Understand Concept 5.2? • What are the differences between peripheral and inThis oocyte has aquaporins inserted experimentally into the cell membrane.
This oocyte does not have aquaporins in the cell membrane.
3.5 minutes in hypotonic solution Water diffuses into the cell through the aquaporin channels, and it swells.
Water does not diffuse into the cell, so it does not swell.
CONCLUSION Aquaporin increases the rate of water diffusion across the cell membrane. ANALYZE THE DATA Oocytes were injected with aquaporin mRNA (red circles) or a solution without mRNA (blue circles). Water permeability was tested by incubating the oocytes in hypotonic solution and measuring cell volume. After time X in the upper curve, intact oocytes were not visible: With mRNA Without mRNA
1.4 1.3 1.2 1.1 1.0
2 3 4 Time (min)
A. Why did the cells increase in volume? B. What happened at time X? C. Calculate the relative rates (volume increase per minute) of swelling in the control and experimental curves. What does this show about the effectiveness of mRNA injection?
For more, go to Working with Data 5.1 at yourBioPortal.com. Go to yourBioPortal.com for original citations, discussions, and relevant links for all INVESTIGATION figures. POL Hillis Sinauer Associates Morales Studio
• What properties of a substance determine whether, and how fast, it will diffuse across a membrane?
• Compare the process of facilitated diffusion through a channel and by a carrier protein. Which might be faster, and why?
• After celery is stored in an open refrigerator for two days, it is wilted. However, immersing the cut stalk in water for a few hours restores the integrity of the celery. How?
Diffusion tends to equalize the concentrations of substances between the outsides and insides of cells or organelles. However, one hallmark of a living thing is that it can have an internal composition quite different from that of its environment. To achieve this, a cell must sometimes move substances against their concentration gradients. This process requires work—the input of energy—and is known as active transport. concept
Some Substances Require Energy to Cross the Membrane
In many biological situations, there is a different concentration of a particular ion or small molecule inside compared with outside a cell. In these cases, the concentration imbalance is maintained by a protein in the plasma membrane that moves the substance against its concentration gradient. This is called active transport, and because it is acting “against the normal flow,” it requires the expenditure of energy. Often the energy source is the nucleotide adenosine triphosphate (ATP). In eukaryotes, ATP is produced in the mitochondria and plastids, and it has chemical energy stored in its terminal phosphate bond. This energy is released when ATP is converted to adenosine diphosphate (ADP) in a hydrolysis reaction that breaks this terminal bond. We will give more details of how ATP provides energy to cells in Concept 6.1. The differences between diffusion and active transport are summarized in Table 5.1.
70 Chapter 5 | Cell Membranes and Signaling
1 The carrier protein has
3 …which then changes
2 Glucose binds to
a glucose binding site.
the protein’s shape…
Outside of cell
High glucose concentration Glucose Rate of diffusion into the cell
to its original shape, ready to bind another glucose.
Active transport is directional Simple and facilitated diffusion follow concentration gradients and can occur in either direction across a membrane. In contrast, active transport is directional, and moves a substance either into or out of a cell or organelle against its concentration gradient. In other words, the substance is transported from a lower to a higher concentration. The direction in which a particular substance is transported depends on the cell’s needs. As in facilitated diffusion, there is usually a specific carrier protein for each substance that is transported.
Different energy sources distinguish different active transport systems LIFE Concepts Sadava There are two basic types of active transport: Sinauer Associates
Studio Primary active transport involves the direct hydrolysis of • Morales Figure 05.06 Date 06-28-10 ATP, which provides the energy required for transport.
In primary active transport, energy released by the hydrolysis of ATP drives the movement of specific ions against their concentration gradients. For example, the concentration of potassium ions (K+) inside
Glucose concentration outside the cell
FIGURE 5.6 A Carrier Protein Facilitates Diffusion The glucose transporter is a carrier protein that allows glucose to enter the cell at a faster rate than would be possible by simple diffusion. (A) The transporter binds to glucose, and as it does so, it changes shape, releasing the glucose into the cell cytoplasm. (B) The graph shows
• Secondary active transport does not use ATP directly. Instead, its energy is supplied by an ion concentration gradient or an electrical gradient, established by primary active transport. This transport system uses the energy of ATP indirectly to set up the gradient.
Some carriers are occupied.
the rate of glucose entry via a carrier versus the concentration of glucose outside the cell. As the glucose concentration increases, the rate of diffusion increases until the point at which all the available transporters are being used (the system is saturated).
a cell is often much higher than the concentration in the fluid bathing the cell. However, the concentration of sodium ions (Na+) is often much higher outside the cell. A protein in the plasma membrane pumps Na+ out of the cell and K+ into the cell against these concentration gradients, ensuring that the gradients are maintained. This sodium–potassium (Na+–K+) pump is an integral membrane glycoprotein that is found in all animal cells. It breaks down a molecule of ATP to ADP and a free phosphate ion (Pi) and uses the released energy to bring two K+ ions into the cell, and export three Na+ ions (FIGURE 5.7).
FRONTIERS Cancer therapy often fails when the targeted cells become resistant to the drugs used to kill them. The drugs may work initially, only to have the cancer return—this time with a membrane protein that actively transports the drugs out of the cells. Designing ways to block this active transport is a major challenge for effective cancer therapy.
TABLE 5.1 Membrane Transport Mechanisms Simple Diffusion
Facilitated diffusion (channel or carrier protein)
Cellular energy required?
ATP hydrolysis (against concentration gradient)
Membrane protein required?
5.2 5.3 Some Substances Require Energy to Cross the Membrane 71
Apply the Concept Some substances require energy to cross the membrane The liver plays several vital metabolic roles, including protein synthesis, detoxification, and the production of substances necessary for digestion. Liver cells are in contact with the blood and exchange a variety of substances with the blood plasma (the noncellular part of blood). Below is a list of observations about the relative concentrations of various molecules in a liver cell cytoplasm and in the blood plasma. Explain each observation in terms of membrane permeability and transport mechanisms.
1. The concentration of serum albumin, a blood protein, is much higher in the plasma.
In secondary active transport, the movement of a substance against its concentration gradient is accomplished using energy “regained” by letting ions move across the membrane with their concentration gradients. For example, once the Na+–K+ pump establishes a concentration gradient of sodium ions, the passive diffusion of some Na+ back into a cell can provide energy for the secondary active transport of glucose into the cell. This occurs when glucose is absorbed into the bloodstream from the digestive tract. Secondary active transport is usually accomplished by a single protein that moves both the ion and the actively
2. The concentration of DNA is much higher in the cytoplasm. 3. The concentration of Na+ is higher in the plasma. 4. The concentration of water is equal in the plasma and the cytoplasm. 5. The concentration of low-density lipoproteins is higher in the cytoplasm. 6. The concentration of glucose is equal in the plasma and the cytoplasm. 7. If K+ enters the plasma, its concentration rapidly equalizes between the plasma and the cytoplasm.
transported molecule across the membrane. In some cases, the ion and the transported molecule move in opposite directions, whereas in others they move in the same direction (as for glucose and Na+ in the digestive tract). Secondary active transport aids in the uptake of amino acids and sugars, which are essential raw materials for cell maintenance and growth.
yourBioPortal.com Go to ANIMATED TUTORIAL 5.2 Active Transport
3 The shape change
4 Release of Pi returns the
releases Na+ outside the cell and enables K+ to bind to the pump.
Outside of cell High Na+ concentration, low K+ concentration
pump to its original shape, releasing K+ to the cell's interior and once again exposing Na+ binding sites. The cycle repeats.
Na+– K+ pump
Inside of cell High K+ concentration, low Na+ concentration
1 3 Na+ and 1 ATP bind to the protein “pump.”
2 Hydrolysis of ATP
phosphorylates the pump protein and changes its shape.
FIGURE 5.7 Primary Active Transport: The Sodium– Potassium Pump In active
transport, energy is used to move a solute against its concentration gradient. Here, energy from ATP is used to move Na+ and K+ against their concentration gradients.
72 Chapter 5 | Cell Membranes and Signaling
Do You Understand Concept 5.3?
• Why is energy required for active transport? • The drug ouabain inhibits the activity of the Na+–K+
Outside of cell Plasma membrane
pump. A nerve cell is incubated in ouabain. Make a table in which you predict what would happen to the concentrations of Na+ and K+ inside and outside the cell, as a result of the action of ouabain.
two ways for glucose to enter a cell: facilitated diffusion via a carrier protein and secondary active transport?
We have examined a number of passive and active ways by which ions and small molecules can enter and leave cells. But what about large molecules such as proteins? Many proteins are so large that they diffuse very slowly, and their bulk makes it difficult for them to pass through the phospholipid bilayer. It takes a completely different mechanism to move intact large molecules across membranes. concept
Inside of cell The plasma membrane surrounds a part of the exterior environment and buds off as a vesicle.
A vesicle fuses with the plasma membrane. The contents of the vesicle are released, and its membrane becomes part of the plasma membrane.
Large Molecules Cross the Membrane via Vesicles Secretory vesicle
Macromolecules such as proteins, polysaccharides, and nucleic acids are simply too large and too charged or polar to pass through biological membranes. This is a fortunate property— cellular integrity depends on containing these macromolecules in specific locations. However, cells must sometimes take up or secrete (release to the external environment) intact large molecules. This is done via vesicles, and the general terms for the mechanisms by which cells take up and secrete large molecules or particles are endocytosis and exocytosis (FIGURE 5.8).
Macromolecules and particles enter the cell by endocytosis Endocytosis is a general term for a group of processes that bring small molecules, macromolecules, large particles, and even small cells into the eukaryotic cell (see Figure 5.8A). There are three types of endocytosis: phagocytosis, pinocytosis, and receptormediated endocytosis. In all three, the plasma membrane invaginates (folds inward), forming a small pocket around materials from the environment. The pocket deepens, forming a vesicle. This vesicle separates from the plasma membrane and migrates with its contents to the cell’s interior.
• In phagocytosis (“cellular eating”), part of the plasma membrane engulfs a large particle or even an entire cell. Unicellular protists use phagocytosis for feeding, and some white blood cells use phagocytosis to engulf foreign cells and substances. The food vacuole (phagosome) that forms usually fuses with a lysosome, where its contents are digested.
LINK Review the discussion of phagocytosis in Concept 4.3 (pp. 53–56)
FIGURE 5.8 Endocytosis and Exocytosis Eukaryotic cells use endocytosis (A) and exocytosis (B) to take up and release large molecules and particles. Even small cells can be engulfed via endocytosis.
• Vesicles also form in pinocytosis (“cellular drinking”). However, in this case the vesicles are smaller and they bring fluids and dissolved substances, including proteins, into the cell. Phagocytosis and pinocytosis are relatively nonspecific regarding what they bring into the cell. For example, pinocytosis goes on constantly in the endothelium—the single layer of cells that separates a blood vessel from the surrounding tissue. Pinocytosis allows cells of the endothelium to rapidly acquire fluids and dissolved solutes from the blood. In receptor-mediated endocytosis, molecules at the cell surLIFE• Concepts Sadava Sinauer Associates face recognize and trigger the uptake of specific materials. Morales Studio Figure 05.08 01-20-10 Let’s take aDate closer look at this last process.
Receptor-mediated endocytosis is specific Receptor-mediated endocytosis is used by animal cells to capture specific macromolecules from the cell’s environment. This process depends on receptors, which are proteins that bind to specific molecules (their ligands) and then set off specific cellular responses. In receptor-mediated endocytosis, the receptors are integral membrane proteins located at particular regions on the extracellular surface of the plasma membrane. These membrane regions are called coated pits because they form slight depressions
5.2 5.4 Large Molecules Cross the Membrane via Vesicles 73
Cytoplasm Outside of cell Specific substance binding to receptor proteins
The protein clathrin coats the cytoplasmic side of the plasma membrane at a coated pit.
The endocytosed contents are surrounded by a clathrin-coated vesicle.
Outside of cell Specific substance binding to receptor proteins
Coated vesicle Clathrin molecules
in the plasma membrane, and their cytoplasmic surfaces are coated by another protein (often clathrin). The uptake process is similar to that in phagocytosis. When the receptors in a coated pit bind to their specific ligands (the macromolecules to be taken into the cell), the coated pit invaginates and forms a coated vesicle around the bound macromolecules. The clathrin molecules strengthen and stabilize the vesicle, which carries the macromolecules away from the plasma membrane and into the cytoplasm (FIGURE 5.9). Once inside, the vesicle loses its clathrin coat and may fuse with a lysosome, where the engulfed material is digested. Because of its specificity for particular macromolecules, receptor-mediated endocytosis is an efficient method for taking up substances that may exist at low concentrations in the cell’s environment. Receptor-mediated endocytosis is the method by which cholesterol is taken up by most mammalian cells. Water-insoluble LIFE Concepts Sadava cholesterol triglycerides are packaged by liver cells into liSinauerand Associates Morales Studio Most of the cholesterol is packaged into lowpoprotein particles. Figure 05.09 Date 06-28-10 density lipoproteins (LDLs) and circulated via the bloodstream. When a particular cell requires cholesterol, it produces specific LDL receptors, which are inserted into the plasma membrane in clathrin-coated pits. LDLs bind to the receptors and are taken into the cell via receptor-mediated endocytosis. Within the resulting vesicle, the LDL particles are freed from the receptors. The receptors segregate to a region that buds off and forms a new vesicle, which is recycled to the plasma membrane. The freed LDL particles remain in the original vesicle, which fuses with a
FIGURE 5.9 Receptor-Mediated Endocytosis The receptor
proteins in a coated pit bind specific macromolecules, which are then carried into the cell by a coated vesicle.
lysosome. There, the LDLs are digested and the cholesterol made available for use by the cell. In healthy individuals, the liver takes up unused LDLs for recycling. People with the inherited disease familial hypercholesterolemia have a deficient LDL receptor in their livers. This prevents receptor-mediated endocytosis of LDLs in the liver, resulting in dangerously high levels of cholesterol in the blood. The cholesterol builds up in the arteries that nourish the heart and causes heart attacks. In extreme cases where only the deficient receptor is present, children and teenagers can have severe cardiovascular disease.
Exocytosis moves materials out of the cell Exocytosis is the process by which materials packaged in vesicles are secreted from the cell (see Figure 5.8B). When the vesicle membrane fuses with the plasma membrane, an opening is made to the outside of the cell. The contents of the vesicle are released into the environment, and the vesicle membrane is smoothly incorporated into the plasma membrane. In Chapter 4 we encounter exocytosis as the last step in the processing of material engulfed by phagocytosis—the release of undigested materials back to the extracellular environment. Secreted proteins are transported out of the cell via exocytosis.
74 Chapter 5 | Cell Membranes and Signaling
The proteins are folded and modified in the endoplasmic reticulum, transported in vesicles to the Golgi where they may be further modified, then packaged in new vesicles for secretion (see Figure 4.7). Exocytosis is important in the secretion of many types of substances, including digestive enzymes from the pancreas, neurotransmitters from neurons, and materials for the construction of the plant cell wall. You will encounter these processes in later chapters.
Autocrine signals bind to receptors on the same cell that secretes them.
Paracrine signals bind to receptors on nearby cells.
Cells without receptors for a particular signal do not respond to that signal.
go to ANIMATED TUTORIAL 5.3 Endocytosis and Exocytosis
• Would a small molecule such as an amino acid enter a cell by receptor-mediated endocytosis?
• Exocytosis involves the fusion of the membranes of a vesicle and the plasma membrane. Explain how this can occur.
We have just introduced the concept of a membrane-bound receptor, which is a key factor in a cell’s interaction with its environment. Let’s look more closely at receptors and how they respond to signals. concept
The Membrane Plays a Key Role in a Cell’s Response to Environmental Signals
A hallmark of living things is their ability to process information from their environment. This information can be thought of in terms of signals. The signal may be a physical stimulus such as light or heat, or a chemical such as a hormone. The mere presence of a signal does not mean a particular cell will respond to it. In order to respond, the cell must have a specific receptor that can detect it. Once the receptor is activated by the signal, it sets off a series of events within the cell. A signal transduction pathway is a sequence of molecular events and chemical reactions that lead to a cell’s response to a signal. The ability of cells to sense and respond to their environment is key to the maintenance of cellular and organismal homeostasis, a theme that recurs throughout our discussion of gene regulation and plant and animal physiology in later chapters of this book.
Cells are exposed to many signals and may have different responses Inside a large multicellular animal, chemical signals made by the body itself reach a target cell by local diffusion or by circulation within the blood. These signals are usually in tiny concentrations (as low as 10–10 M) and differ in their sources and mode of delivery (FIGURE 5.10):
Circulating signals such as hormones are transported by the circulatory system and bind to receptors on distant cells.
Circulatory vessel (e.g., a blood vessel)
FIGURE 5.10 Chemical Signaling Concepts A signal molecule
can act on the cell that produces it, a nearby cell, or be transported by the organism’s circulatory system to a distant target cell.
• Autocrine signals affect the same cells that release them. For example, many tumor cells reproduce uncontrollably because they self-stimulate cell division by making their own division signals. • Paracrine signals diffuse to and affect nearby cells. An example is a neurotransmitter made by one nerve cell that diffuses to an adjacent cell and stimulates it. • Signals to distant cells travel through the circulatory system and are called hormones. Chemical signals do not always come from within the multicelLIFE Concepts Sadava come from the external environment. For lular organism—some Sinauer Associates example, specific molecules produced by pathogenic organisms Morales Studio trigger signal transduction Figure 05.10 Date 12-27-09 pathways in plants, leading to defense responses. For the information from a signal to be transmitted to a cell, the target cell must be able to sense the signal and respond to it. In a multicellular animal, all the cells may receive chemical signals that are circulated in the blood, but most body cells are not capable of responding to the signals. Only the cells with the necessary receptors can respond. Typically, a signal transduction pathway involves a signal, a receptor, and a response (FIGURE 5.11). These pathways vary
5.2 5.5 The Membrane Plays a Key Role in a Cell’s Response to Environmental Signals 75
Growth factor (ligand) fits noncovalently into receptor.
1 A signal moelcule Signal molecule
arrives at the target cell.
2 A signal molecule binds to a receptor protein in the cell surface or inside the cytoplasm. Two receptor subunits are transmembrane proteins.
Outside of cell 3 Signal binding changes the three-dimensional shape of the receptor and exposes its active site.
Short-term changes: enzyme activation, cell movement Inactive signal transduction molecule
Inside of cell
Activated signal transduction molecule
4 The activated receptor activates a signal transduction pathway to bring about cellular changes.
Long-term changes: altered DNA transcription
FIGURE 5.11 Signal Transduction Concepts This general pathway is common to many cells and situations. The ultimate cellular responses are either short-term, long-term, or both.
in their details, but a common mechanism is allosteric regulation. Recall that allosteric regulation involves an alteration in the three-dimensional shape of a protein as a result of the binding of another molecule at a site other than the protein’s active site (see Chapter 3). You have already seen an example of allosteric regulation in this chapter when we considered a gated channel, which opens (changes shape) after binding to another molecule (see Figure 5.6). A signal transduction pathway may end in a response that is short term, such as the activation of an enzyme, or long term, such as an alteration in gene expression. POL Hillis Sinauer Associates Morales Studio proteins act Membrane Figure 05.11 Date 06-15-10
A cell must have the appropriate receptor in order to respond to a signal. The signal may be a specific molecule or physical stimulus. In the following discussion, we will focus on chemical signals, such as those described in the previous section. The signal molecule fits into a three-dimensional site on its corresponding receptor protein (FIGURE 5.12). As noted earlier in the chapter, a molecule that binds to a receptor in this way is called a ligand. Binding of the ligand causes the receptor to change its three-dimensional shape, and that conformational change initiates a cellular response. In many cases, the receptor has an enzyme function (a catalytic domain), with its active site on the cytoplasmic side of the membrane. When the ligand
FIGURE 5.12 A Signal Binds to Its Receptor Human growth factor fits into its membrane-bound receptor and binds to it noncovalently. There is an equilibrium between bound and unbound receptor.
binds to the receptor (for example, on the outside of the cell), the ligand acts as an allosteric regulator, exposing the active site of the catalytic domain. Generally, the ligand does not contribute further to the cellular response. In fact, the ligand is usually not metabolized (or changed) at all; its role is purely to “knock on the door.” (This is in sharp contrast to enzyme–substrate interactions, which we describe in Chapter 3. The whole purpose of those interactions is to change substrates into useful products.) Receptors (R) bind to their ligands (L) noncovalently, according to chemistry’s law of mass action: Signal molecule Receptor
LIFE Concepts Sadava Sinauer Associates Morales Studio Figure 05.12 Date 12-27-09 R+L
This means the binding is reversible, although for most ligand– receptor complexes, the equilibrium point is far to the right of the above reaction—that is, binding is favored. Reversibility is important, however, because if the ligand were never released, the receptor would be continuously stimulated. An inhibitor (or antagonist) can also bind to a receptor protein, preventing the binding of the normal ligand. This is analogous to the competitive inhibition of enzymes (see Chapter 3). There are both natural and artificial antagonists of receptor binding. For example, many substances that alter human behavior bind to specific receptors in the brain and prevent the binding of the receptors’ specific ligands.
76 Chapter 5 | Cell Membranes and Signaling
Receptors can be classified by location and function The chemistry of signal ligands is quite variable, but they can be divided into two groups based on whether or not they can diffuse through membranes. Correspondingly, a receptor can be classified by its location in the cell, which largely depends on the nature of its ligand:
• Cytoplasmic receptors. Small or nonpolar ligands can diffuse across the phospholipid bilayer of the plasma membrane and enter the cell. Estrogen, for example, is a lipid-soluble steroid hormone that can easily diffuse across the plasma membrane; it binds to a receptor in the cytoplasm. Many cytoplasmic receptors function as regulators of gene expression; they alter (upregulate or downregulate) the expression of specific genes as a result of ligand binding. • Membrane receptors. Large or polar ligands cannot cross the lipid bilayer. Insulin, for example, is a protein hormone that cannot diffuse through the plasma membrane. Instead, it binds to a transmembrane receptor with an extracellular binding domain.
FRONTIERS Membrane proteins are not always evenly distributed. For example, some receptors are concentrated in a particular area, trapped in a lipid raft—a semisolid region with lipids enriched in cholesterol and long-chain fatty acids. How do these rafts get placed where they are, and how do they trap only certain proteins? Scientists are investigating membrane assembly in the endoplasmic reticulum and Golgi apparatus to find out. This information will be important for understanding how cells optimize functions such as cell signaling. In complex eukaryotes such as mammals and higher plants, there are three well-studied categories of plasma membrane receptors, which are grouped according to their activities: ion channels, protein kinase receptors, and G protein–linked receptors. Because you will see these receptors several times later in the text, we describe them in some detail here. ion channel receptors As described in Concept 5.2, the plasma membranes of many cells contain gated ion channels for ions such as Na+, K+, Ca2+, or Cl– (see Figure 5.4). The gate-opening mechanism is an alteration in the three-dimensional shape of the channel protein upon ligand binding; thus these proteins function as receptors. An example is the acetylcholine receptor, a ligand-gated sodium channel located in the plasma membranes of skeletal muscle cells. The ligand acetylcholine is a neurotransmitter—a chemical signal released from neurons. Opening of the channel allows Na+, which is more concentrated outside the cell than inside, to diffuse into the cell. This initiates a series of events that result in muscle contraction (see Figure 34.9). protein kinase receptors Like gated channel receptors, pro-
tein kinase receptors change shape upon ligand binding. But in this case, the new conformation exposes or activates a domain on the cytoplasmic side of the transmembrane protein that has catalytic (protein kinase) activity (FIGURE 5.13).
1 The receptor binds the signal.
2 A conformational change in the receptor transmits the signal to the cytoplasm.
Outside of cell
3 The signal activates Protein kinase domain (inactive)
the receptor’s protein kinase domain in the cytoplasm…
P P P P
4 …which phos-
phorylates targets, triggering a cascade of chemical responses inside the cell.
Inside of cell
FIGURE 5.13 A Protein Kinase Receptor The mammalian hormone insulin binds to a protein kinase receptor on the outside surface of the cell and initiates a response.
In general, protein kinases catalyze the following reaction: ATP + protein → ADP + phosphorylated protein Each protein kinase has specific target(s) in the cell. The reaction results in the covalent modification (phosphorylation) of a target protein, thereby changing its activity. Protein kinases are extraordinarily important in biological signaling: about 1 human gene in 50 is a protein kinase, and there is an even higher proportion of such genes in some plants. POL Hillis An example Sinauer Associatesof a protein kinase receptor is that for the horMorales Studio The activation of this receptor results in the phosmone insulin. Figure 05.13 Date 06-15-10 phorylation of target proteins in the cytoplasm. The targeted proteins mediate the cell’s response, which includes the insertion of glucose transport proteins into the cell membrane. It should be noted that not all protein kinases are receptors— many function in later steps of signal transduction pathways. In these cases, the protein kinase is activated by a receptor or other protein, and then phosphorylates the next protein in the pathway (see Concept 5.6). g protein–linked receptors A third category of eukaryotic plasma membrane receptors is the family of G protein–linked receptors. In this case, ligand binding on the extracellular domain of the receptor changes the shape of its cytoplasmic region, exposing a site that can bind to a mobile membrane protein called a G protein. The G protein is partially inserted in the lipid bilayer and partially exposed on the cytoplasmic surface of the membrane. Many G proteins have three polypeptide subunits and can bind three different molecules:
5.2 5.6 Signal Transduction Allows the Cell to Respond to Its Environment 77
1 The G protein and effector
protein are inactive until the signal arrives.
Outside of cell
2 Hormone binding to the receptor activates the G protein. GTP replaces GDP.
3 Part of the activated G protein activates an effector protein that converts thousands of reactants to products, thus amplifying the action of a single signal molecule.
Signal (hormone) Activated effector protein
G proteinlinked receptor
Inactive G protein
Inactive effector protein
3 The GTP on the G
Activated G protein
protein is hydrolyzed to GDP but remains bound to the protein.
FIGURE 5.14 A G Protein–Linked Receptor The G protein is an intermediary between the receptor and an effector.
• The receptor • GDP and GTP (guanosine diphosphate and triphosphate, respectively; these are nucleotides used for energy transfer, like ADP and ATP) • An effector protein (a protein that causes an effect in the cell) The activated G protein–linked receptor functions as a guanine nucleotide exchange factor, which exchanges a GDP nucleotide bound to the G protein for a more energy-rich GTP. The activated G protein in turn activates the effector protein, leading to downstream signal amplification (FIGURE 5.14). G protein– linked receptors are especially important in the sensory systems of animals (see Chapter 35). LIFE Concepts Sadava yourBioPortal.com Sinauer Associates go to ANIMATED TUTORIAL 5.4 Morales Studio Protein–Linked Signal Transduction and Cancer FigureG05.14 Date 12-27-09
Do You Understand Concept 5.5? • What are the three major steps in cell signaling? • What are the differences and similarities between ion channel receptors and G protein–linked receptors?
• If an intact cell is treated with an enzyme that hydro-
lyzes proteins, what will be the resulting composition of the plasma membrane? Will the cell be able to receive any environmental signals?
Regardless of the type of receptor, when a signal activates it, a signal transduction pathway ensues. This often involves a series of multiple steps, and it leads to a particular cellular response. This could be the expression of a set of genes that were previously silent. The proteins encoded by these genes change the cell in some way so it can respond to the signal.
Signal Transduction Allows the Cell to Respond to Its Environment
As we mentioned in Concept 5.5, a signal may be a chemical ligand or a physical stimulus such as light or heat. Its effect is to activate a specific receptor—leading to a cellular response, which is mediated by a signal transduction pathway. Typically, signaling at the plasma membrane initiates a cascade (series) of events in the cell, in which proteins interact with other proteins until the final responses are achieved. Through such a cascade, an initial signal can be both amplified and distributed to cause several different responses in the target cell.
Second messengers can stimulate signal transduction Often there is a small molecule intermediary between the activated receptor and the cascade of events that ensues. In a series of clever experiments, Earl Sutherland and his colleagues at Case Western Reserve University discovered that a small water-soluble chemical messenger can mediate the cytoplasmic events initiated by a plasma membrane receptor. These researchers were investigating the activation of the liver enzyme glycogen phosphorylase by the hormone epinephrine (also called adrenaline)— the “fight-or-flight” hormone. The enzyme is activated when an animal faces life-threatening conditions and needs energy fast for the fight-or-flight response. Glycogen phosphorylase catalyzes the breakdown of glycogen stored in the liver so that the resulting glucose molecules can be released to the blood (see Figure 30.10). The enzyme is present in the liver cell cytoplasm but is inactive in the absence of epinephrine. The researchers found that epinephrine could activate glycogen phosphorylase in liver cells that had been broken open, but only if the entire cell contents, including plasma membrane fragments, were present. Under these conditions epinephrine was bound to the plasma membrane fragments, but the active phosphorylase was present in the solution. The researchers hypothesized that there must be a second “messenger” that transmits the
INVESTIGATION FIGURE 5.15 The Discovery of a Second Messenger Glycogen phosphorylase is activated in liver cells after epinephrine binds to a membrane receptor. Sutherland and his colleagues observed that this activation could occur in vivo only if fragments of the
plasma membrane were present. They designed experiments to show that a second messenger caused the activation of glycogen phosphorylase.
HYPOTHESIS A second messenger mediates between receptor activation at the plasma membrane and enzyme activation in the cytoplasm. RESULTS METHOD Active glycogen phosphorylase is present in the cytoplasm. Liver
2 The hormone epinephrine is added to the membranes and allowed to incubate.
2 4 Drops of
3 The membranes
membrane-free solution are added to the cytoplasm.
are removed by centrifugation, leaving only the solution in which they were incubated.
A soluble second messenger, produced by hormoneactivated membranes, is present in the solution and activates enzymes in the cytoplasm. ANALYZE THE DATA The activity of previously inactive liver glycogen phosphorylase was measured with and without epinephrine incubation, with these results: Condition
A. What do these data show? B. Propose an experiment to show that the activation of the enzyme is stable on heating and give predicted data. C. Propose an experiment to show that cAMP can replace the particulate fraction and hormone treatment and give predicted data.
For more, go to Working with Data 5.2 at yourBioPortal.com.
Go to yourBioPortal.com for original citations, discussions, and relevant links for all INVESTIGATION figures. epinephrine signal (the “first messenger”) to the phosphorylase in the cytoplasm. They investigated this by separating plasma membrane fragments from the cytoplasmic fractions of broken liver cells and followed the sequence of steps described in FIGURE 5.15. This experiment confirmed the existence of a second messenger. Later, the second messenger was identified as cyclic AMP (cAMP; FIGURE 5.16). Second messengers do not have enzymatic activity themselves; rather, they act to regulate target enzymes by binding to them noncovalently.
LINK Review the ways that enzymes are regulated in Concept 3.4 (pp. 42–44) A second messenger is a small molecule that mediates later steps in a signal transduction pathway. While receptor binding is highly specific, second messengers allow a cell to respond to a single event at the plasma membrane with many events inside POL Hillis Sinauer FIGUREAssociates 5.16 The Formation of Cyclic AMP The formation of Morales Studio cAMP from ATP is catalyzed by adenylyl cyclase, an enzyme that is Figure 5.15by Date 06-24-10 activated G proteins.
P O P O P O CH2 O O– O– O– H H HC
O CH O
Cyclic AMP (cAMP)
5.2 5.6 Signal Transduction Allows the Cell to Respond to Its Environment 79 the cell—in other words, the second messenger distributes the initial signal. Second messengers also serve to amplify the signal—for example, the binding of a single epinephrine molecule leads to the production of many molecules of cAMP. In turn, cAMP activates many enzyme targets by binding to them noncovalently. In the case of epinephrine and the liver cell, glycogen phosphorylase is just one of several enzymes that are activated.
A signaling cascade involves enzyme regulation and signal amplification Signal transduction pathways often involve multiple sequential steps, in which particular enzymes are either activated or inhibited by other enzymes in the pathway. For example, a protein kinase adds a phosphate group to a target protein, and this covalent change alters the protein’s conformation and activates or inhibits its function. Cyclic AMP binds noncovalently to a target protein, and this changes the protein’s shape, activating or inhibiting its function. In the case of activation, a previously inaccessible active site is exposed, and the target protein goes on to perform a new cellular role. A good example of a signaling cascade is the G protein– mediated protein kinase pathway stimulated by epinephrine in liver cells (FIGURE 5.17). Binding of epinephrine to the membrane receptor results in the activation of a G protein, followed by the production of cAMP, which activates a key signaling molecule, protein kinase A. In turn, protein kinase A phosphorylates two other enzymes, with opposite effects: • Inhibition. Glycogen synthase, which catalyzes the joining of glucose molecules to form the energy-storing molecule glycogen, is inactivated when a phosphate group is added to it by protein kinase A. Thus the epinephrine signal prevents glucose from being stored in glycogen (Figure 5.17, step 1). • Activation. Phosphorylase kinase is activated when a phosphate group is added to it. It is part of a cascade of reactions that ultimately leads to the activation of glycogen phosphorylase, another key enzyme in glucose metabolism. This enzyme results in the liberation of glucose molecules from glycogen (Figure 5.17, steps 2 and 3). An important consequence of having multiple steps in a signal transduction cascade is that the signal is amplified with each step. The amplification of the signal in the pathway illustrated in Figure 5.17 is impressive. Each molecule of epinephrine that arrives at the plasma membrane ultimately results in 10,000 molecules of blood glucose: 1 molecule of epinephrine bound to the membrane activates 20 molecules of cAMP, which activate 20 molecules of protein kinase A, which activate 100 molecules of phosphorylase kinase, which activate 1,000 molecules of glycogen phosphorylase, which produce 1 0,000 molecules of glucose 1-phosphate, which produce 10,000 molecules of blood glucose
Outside of cell
Activated G protein subunit
1 Phosphorylation, induced
Activated adenylyl cyclase
by epinephrine binding, inactivates glycogen synthase, preventing glucose from being stored as glycogen.
cascade amplifies the signal. Here, for every molecule of epinephrine bound, 20 molecules of cAMP are made, each of which activates a molecule of protein kinase A.
4 Release of glucose fuels “fight-or-flight” response.
Outside of cell
FIGURE 5.17 A Cascade of Reactions Leads to Altered Enzyme Activity Liver cells respond to epinephrine by activat-
ing G proteins, which in turn activate the synthesis of the second messenger cAMP. Cyclic AMP initiates a protein kinase cascade, greatly amplifying the epinephrine signal, as indicated by the blue numbers. The cascade both inhibits the conversion of glucose to glycogen and stimulates the release of previously stored glucose.
yourBioPortal.com go to ANIMATED TUTORIAL 5.5 Signal Transduction Pathway
Signal transduction is highly regulated Signal transduction is a temporary event in the cell, and gets
LIFE The Science of Biology 9E Sadava “turned off” once the cell has responded. To regulate protein Sinauer Associates kinases, G proteins, and cAMP, there are enzymes that convert Morales Studio Figure 07.20 Date 04-20-09 each activated transducer back to its inactive precursor (FIGURE
5.18). The balance between the activities of these regulating enzymes and the signaling enzymes themselves is what determines the ultimate cellular response to a signal. Cells can alter this balance in several ways:
FIGURE 5.18 Signal Transduction Regulatory Mechanisms Some signals lead to the production of active transducers such as (A) protein kinases, (B) G proteins, and (C) cAMP. Other enzymes (red type) inactivate or remove these transducers.
• Synthesis or breakdown of the enzymes involved. For example, synthesis of adenylyl cyclase and breakdown of phosphodiesterase (which breaks down cAMP) would tilt the balance in favor of more cAMP in the cell. • Activation or inhibition of the enzymes by other molecules. Examples include the activation of a G protein–linked receptor by ligand binding, and inhibition of phosphodiesterase (which also breaks down cGMP) by sildenafil citrate (Viagra), a drug used to treat erectile dysfunction.
Cell functions change in response to environmental signals LIFE Concepts Sadava The activation of a receptor by a signal, and the subsequent Sinauer Associates Morales Studio transduction and amplification of the signal, ultimately leads to Figure 05.17 Date 12-27-09 changes in cell function. There are many ways in which a cell
might respond. Three important types of responses have already been discussed in this chapter: • Opening of ion channels changes the balance of ion concentrations between the outside of the cell and its interior (see Figure 5.4). As you will see in Chapter 34, this results in a change in the electrical potential across the membrane, with important consequences in nerve and muscle cells. • Many signal transduction pathways lead to alterations in gene expression. The expression of some genes may be switched on (upregulated), whereas others are switched off (downregulated). This alters the abundance of the proteins (often enzymes) encoded by the genes, thus changing cell function. You will see many examples that highlight the importance of gene regulation throughout this book. • A third kind of response involves the alteration of enzyme activities. An example is the activation of phosphorylase kinase and
the inhibition of glycogen synthase in liver cells exposed to epinephrine (see Figure 5.17). In this case, the signal transduction pathway does not lead to alterations in the expression of the genes that encode these enzymes. Their activities are regulated so that the liver cell can rapidly supply energy-rich glucose for the fight-or-flight response. Different signal transduction pathways can produce different cellular responses to the same signal-receptor binding event. An example is the responses to epinephrine in heart muscle and in the smooth muscles that line blood vessels. When epinephrine binds to its receptor in heart muscle cells, a G protein is activated that in turn activates the signal transduction cascade that results in glucose mobilization for energy and muscle contraction (see Figure 5.17). In smooth muscle cells that line the digestive tract, however, a different G protein gets activated by epinephrine receptor binding, and in this case the G protein inhibits a target enzyme, allowing the muscle cells to relax. This increases the diameter of the blood vessels, allowing more nutrients to be carried from the digestive system to the rest of the body. (For more on the flight-or-fight response, see Chapter 30.) So the same signaling mechanism can lead to different responses. A great deal has been learned about signal transduction pathways and cellular responses in the past two decades, and there is still much to learn. As biologists tease apart specific pathways, they find that many of them are interconnected: one pathway may be switched on by a particular signal or molecule, and another may be switched off. In this chapter we have concentrated on signaling pathways that occur in animal cells. However, signal transduction pathways are important in the functioning of all living organisms.
Do You Understand Concept 5.6? • Compare “first messengers” (e.g., hormones) with “second messengers” (e.g., cAMP) with regard to their chemical nature, where and when they are made, and locations of synthesis and activity.
• Outline the steps in the amplification of signaling by
epinephrine, resulting in the release of glucose to the bloodstream. At each step, is the amplification due to a covalent or noncovalent interaction?
• What would happen to a liver cell exposed to epi-
nephrine and at the same time to a drug that inhibits protein kinase A? To epinephrine and to a drug that inhibits the hydrolysis of GTP?
• Biochemist Robert Furchgott studied how acetyl-
choline, released from nerve cells, causes smooth muscles surrounding arteries to relax, dilating the arteries. He found that the smooth muscles in an intact artery section would relax, but if the endothelial cells lining the blood vessel were removed, the addition of acetylcholine would not cause dilation. A second messenger was proposed. How would you investigate this hypothesis?
5.2 5.6 Signal Transduction Allows the Cell to Respond to Its Environment 81 (B)
(A) Outside of cell Plasma membrane
The adenosine receptor occurs in the brain cells. Adenosine and caffeine both fit the receptor.
The similar structures of caffeine and adenosine allow them both to bind to the receptor, but only adenosine triggers signal transduction.
FIGURE 5.19 Caffeine and the Cell Membrane (A) The adenosine 2A receptor is present in the human brain, where it is involved in inhibiting arousal. (B) Adenosine is the normal ligand for the receptor. Caffeine has a structure similar to that of adenosine and can act as an antagonist that binds the receptor and prevents its normal functioning.
What role does the cell membrane play in the body’s response to caffeine?
Caffeine has many effects on the body, but the most noticeable is that it keeps us awake. The caffeine molecule is somewhat large and polar, and it is unlikely to diffuse through the nonpolar lipids of the cell membrane (Concept 5.2). Instead, it binds to receptors on the surfaces of nerve cells in the brain (Concept 5.5). The nucleoside adenosine (adenine attached to a five-carbon sugar) accumulates in the brain when a person is under stress or has prolonged mental activity. When it binds to a specific receptor in the brain, adenosine sets in motion a signal transduction pathway (Concept 5.6) that results in reduced brain activity, which usually means drowsiness. This membrane-associated signaling by adenosine has evolved as a protective mechanism against the adverse effects of stress.
LIFE The Science of Biology 9E Sadava Sinauer Associates Morales Studio Figure 07.04 Date 05-18-09
Caffeine has a three-dimensional structure similar to that of adenosine, and is able to bind to the adenosine receptor (FIGURE 5.19). Because its binding does not activate the receptor, caffeine functions as an antagonist of adenosine signaling, with the result that the brain stays active and the person remains alert. When we discussed the interaction between a ligand and its receptor, we noted that this is a reversible, noncovalent interaction. In time, after drinking coffee or tea, the caffeine molecules come off the adenosine receptors in the brain, allowing adenosine to bind once again. Otherwise, coffee drinkers might never get to sleep! In addition to competing with adenosine for a membrane receptor, caffeine blocks the enzyme cAMP phosphodiesterase. This enzyme acts in signal transduction (Concept 5.6) to break down the second messenger cAMP. Looking at the signal transduction pathway in Figure 5.17, can you explain how caffeine augments the fight-or-flight response, which includes an increase in blood sugar and increased heartbeat?
82 Chapter 5 | Cell Membranes and Signaling
SUMMARY Biological Membranes Have a Common Structure and Are Fluid
• Biological membranes consist of lipids, proteins, and carbo-
hydrates. The fluid mosaic model of membrane structure describes a phospholipid bilayer in which proteins can move about within the plane of the membrane.
• The two layers of a membrane may have different properties
because of their different phospholipid compositions, exposed domains of integral membrane proteins, and peripheral membrane proteins. Transmembrane proteins span the membrane. Review Figure 5.1, WEB ACTIVITY 5.1, and INTERACTIVE TUTORIAL 5.1
Some Substances Can Cross the Membrane by Diffusion
• Membranes exhibit selective permeability, regulating which substances pass through them.
• A substance can diffuse passively across a membrane by one of two processes: simple diffusion through the phospholipid bilayer or facilitated diffusion, either through a channel created by a channel protein or by means of a carrier protein. In both cases, molecules diffuse down their concentration gradients. • In osmosis, water diffuses from a region of higher water concentration to a region of lower water concentration through membrane channels called aquaporins. Ions diffuse across membranes through ion channels. Review Figures 5.3 and 5.4, ANIMATED TUTORIAL 5.1, and WORKING WITH DATA 5.1
• Carrier proteins bind to polar molecules such as sugars and
amino acids and transport them across the membrane. Review Figure 5.6
Some Substances Require Energy to Cross the Membrane
• Active transport requires the use of chemical energy to move
substances across membranes against their concentration gradients. The sodium–potassium (Na+–K+) pump uses energy released from the hydrolysis of ATP to move ions against their concentration gradients. Review Figure 5.7 and ANIMATED TUTORIAL 5.2
Large Molecules Cross the Membrane via Vesicles
• Endocytosis is the transport of small molecules, macromol-
ecules, large particles, and small cells into eukaryotic cells via the invagination of the plasma membrane and the formation of vesicles. Review Figure 5.8A
• In receptor-mediated endocytosis, a specific receptor on
the plasma membrane binds to a particular macromolecule. Review Figure 5.9 and ANIMATED TUTORIAL 5.3
• In exocytosis, materials in vesicles are secreted from the cell when the vesicles fuse with the plasma membrane. Review Figure 5.8B
The Membrane Plays a Key Role in a Cell’s Response to Environmental Signals
• Cells receive many signals from the physical environment and from other cells. Chemical signals are often at very low concentrations. Review Figure 5.10
• A signal transduction pathway involves the interaction of a
signal (often a chemical ligand) with a receptor; the transduction and amplification of the signal via a series of steps within the cell; and a cellular response. The response may be shortterm or long-term. Review Figure 5.11
• Cells respond to signals only if they have specific receptor pro-
teins that can be activated by those signals. Most receptors are located at the plasma membrane. They include ion channels, protein kinases, and G protein–linked receptors. Review Figures 5.13 and 5.14 and ANIMATED TUTORIAL 5.4
Signal Transduction Allows the Cell to Respond to Its Environment
• A cascade of events, one following another, occurs after a receptor is activated by a signal.
• Often, a soluble second messenger conveys signaling informa-
tion from the primary messenger (ligand) at the membrane to downstream signaling molecules in the cytoplasm. Cyclic AMP (cAMP) is an important second messenger. Review Figure 5.16 and WORKING WITH DATA 5.2
• Activated enzymes may in turn activate other enzymes in a signal transduction pathway, leading to impressive amplification of a signal. Review Figure 5.17 and ANIMATED TUTORIAL 5.5
• Protein kinases covalently add phosphate groups to target
proteins; cAMP binds target proteins noncovalently. Both kinds of binding change the target protein’s conformation to expose or hide its active site.
• Signal transduction can be regulated in several ways. The bal-
ance between the activation and inactivation of the molecules involved determines the ultimate cellular response to a signal. Review Figure 5.18
• The cellular responses to signals may include the opening of
ion channels, changes in gene expression, or the alteration of enzyme activities.
See WEB ACTIVITY 5.2 for a concept review of this chapter.