The plasma membrane, or cell membrane, separates the cytoplasm from the surrounding extracellular fluid (ECF). The fluid part of the cytoplasm, called the cytosol (SĪ-to-sōl), has different chemical properties than the ECF, and maintaining these differences is essential to the life of a cell. The plasma membrane maintains the cytosol’s chemical properties by regulating the types and amounts of molecules that enter or leave the cell. Moreover, features on the surface of the plasma membrane enable cells to interact with each other. Often, these surface features allow the cell to respond in a specific way when chemical triggers (such as hormones) appear in the ECF.
A cell’s plasma membrane isn’t a solid sheet like the transparent plastic wrap that you might use to cover a dish of leftovers. Like a mosaic, a picture made of tiny pieces, the plasma membrane is an assembly of macromolecules. In fact, it behaves more like a liquid because the plasma membrane’s individual pieces can spin around and slide past each other. For this reason, biochemists call plasma membranes fluid mosaics. The structure and composition of a plasma membrane isn’t static, either. Molecules constantly shuttle back and forth between the cytoplasm and plasma membrane. This steady flow of “molecular traffic” promotes survival, allowing a cell to change the makeup of its plasma membrane in order to adapt to changing conditions. Look at Figure 6-1 to see the fluid mosaic plasma membrane.
Figure 6.1: The plasma membrane
MEMBRANE LIPIDS
Lipids account for less than half of the plasma membrane’s weight, but they account for about 99 percent of the membrane’s molecules. The two most abundant lipids in the plasma membrane of a human cell are phospholipids and cholesterol.
Phospholipids: A plasma membrane is a bilayer (two layers) of phospholipid molecules. Half of the bilayer faces the ECF while the other half faces the cytosol. Other amphipathic, having parts that have opposite or dissimilar chemical properties. Each phospholipid molecule has a polar, hydrophilic (“water-loving”) head made of macromolecules tunnel through the bilayer or cling to either face. Phospholipids are glycerol and two nonpolar, hydrophobic (“water- fearing”) tails made of long fatty-acid chains.
The amphipathic properties of phospholipid molecules enable them to self-organize into a bi- layer. The slender fatty-acid tails cluster together in the center of the bilayer, forming a hydrophobic zone that squeezes out water and water-soluble substances. At the same time, the hydrophilic heads seek out the watery extracellular fluid or cytosol. The combined hydrophobic and hydrophilic attractions “pull” the bilayer into shape. But since the phospholipid molecules do not chemically bond to each other, they are free to spin on their axes and slide past one another, actions that give the plasma membrane its fluid properties. Membrane phospholipids rarely turn somersaults, however, so they do not flip-flop from one face of a bilayer to the other.
Note:
Model the lipid bilayer by drawing together the fingertips on each hand, and then move both hands together so the facing fingertips overlap near the distal finger joints. Since fatty-acid tails are always moving, wiggle your fingers a bit to set the model in motion.
Functionally, the amphipathic qualities of phospholipids are what make the plasma mem- brane an effective chemical barrier. The hydrophobic zone at the membrane’s center largely prevents water molecules and water-soluble substances (including ions) from darting back and forth be- tween the extracellular fluid and cytosol. At the same time, the polar hydrophilic heads on each face of the membrane tend to repel fat-soluble and non-ionized substances. The fluid-like nature of the plasma membrane is due primarily to the phospholipid molecules, and is important to the cell in three ways:
- A plasma membrane is self-repairing: Imagine the glycerol heads of the phospholipids as an unbroken sheet of ping-pong balls floating in a bucket of water. The balls move apart if you plunge your hand into the water then come together again as you pull back your hand. Like the ping-pong balls, if a few phospholipid molecules are bumped apart in the bilayer, they pull back together quickly, resealing the membrane.
- A plasma membrane is flexible: Membrane fluidity enables a cell to ingest large particles, to change shape, and to divide during cellular reproduction. A white blood cell, for example, traps invading microorganisms by encircling them with its plasma membrane. Oxygen-carrying red blood cells can squeeze through the narrowest blood vessels without rupturing. When it is time for a cell to repro- duce, the plasma membrane’s fluidity allows the cell to pinch itself in two without exposing the cytoplasm to the extracellular fluid.
- A plasma membrane readily changes size: Because “fat attracts fat,” new phospholipids easily join the plasma membrane. You can witness a similar process by observing how the tiny fat droplets on the surface of a bowl of hot chicken soup eventually combine into a few large fat globules. The cytoplasm inserts or retrieves phospholipids from the plasma membrane in tiny hollow spheres called vesicles. In this way, the plasma membrane can enlarge as the cell grows, or it can supply molecules for use elsewhere inside the cell.
Cholesterol: Like tiny cars wedged between trucks in a parking lot, slender cholesterol molecules tuck themselves between the larger phospholipids along both faces of the plasma membrane. Given the frequent new reports about the dangers of excessive levels of cholesterol in the blood, is the cholesterol in a cell’s plasma membrane a good thing? The answer is yes, because cholesterol stabilizes the fluidity of the membrane when the temperature changes. At low temperatures, fatty acids tend to pack together and stiffen. (This is why butter, which is high in fat, hardens in the refrigerator.) On a frigid day, a skin cell may be far colder than the body’s core temperature. However, cholesterol in the skin cell’s plasma membrane prevents membrane phospholipids from bunching up, keeping the membrane flexible. This is one reason why your skin doesn’t quickly crack open when exposed to freezing temperatures. Cholesterol also stabilizes the plasma membrane when the cell is warmer than the body’s average temperature. At higher temperatures, fatty acids become even more fluid-like. (This is why butter melts in a pan on the stove.) So why doesn’t the plasma membrane of skin cells “melt” if you have a fever or if you soak in a hot bath? In these situations, cholesterol molecules act like tiny anchors, snagging nearby fatty acid tails of the phospholipid molecules and slowing their side- to-side movement within the membranes. As you might have guessed, a cell controls the stiffness of its plasma membrane by adding or removing cholesterol molecules as conditions change.
MEMBRANE CARBOHYDRATES
A host of carbohydrates extends like tree branches from the extracellular face of the plasma membrane. Membrane carbohydrates are typically oligosaccharides (ol-i-gō-SAK-ar-īdz; oligo, few), short chains of simple sugars. Some oligosaccharides bond directly to membrane phospholipids forming glycolipids. More often, however, oligosaccharides bond to proteins that project from the membrane, forming glycoproteins.
All of the carbohydrate molecules that project from the extracellular face of the plasma membrane comprise the cell’s glycocalyx (glī-kō- KĀ-lix; glyco, sugar; calyx, coat). The configuration of the glycocalyx differs according to cell type. Hence, the glycocalyx, along with proteins in the plasma membrane, give a cell a distinctive chemical nature by which other cells recognize it. The glycocalyx is the basis of cellular recognition, which guides how cells join to form distinct tissues and organs. The body’s immune system cells also rely on cellular recognition to detect and kill “foreign” cells, such as bacteria that may enter the body.
The importance of the plasma membrane’s glycocalyx cannot be overstated. The body begins forming because a sperm cell recognizes the glycocalyx of an ovum (egg cell). Liver cells stay put in the liver because their glycocalyces (glī-kō- KĀ-li-sēz) hold them together. Too, the presence (or absence) of specific oligosaccharides in the glycocalyx of red blood cells determines a person’s blood type. If someone receives an incompatible blood type during a transfusion, the recipient’s immune system identifies the donated blood cells as having “foreign” glycocalyces and destroys them.
In addition to allowing cell recognition, the glycocalyx also protects cells from damage. For example, water readily sticks to the glycocalyx and makes the surface of some cells very slippery. The glycocalyx greatly reduces friction as red blood cells slide past one another inside tiny blood vessels. A slippery glycocalyx also allows certain white blood cells to squeeze out of blood vessels and prowl through the surrounding tissues in search of invading microorganisms and viruses.
MEMBRANE PROTEINS
Although not nearly as numerous as lipid molecules, proteins contribute more than 50 percent of the plasma membrane’s weight. Each type of protein in the membrane has a unique size, shape, and chemical structure that is suited to its particular role.
Classification by Location
Cell biologists divide plasma membrane proteins into two categories based on their physical relationship to the membrane.
- Integral proteins anchor to the inner, hydro- phobic layer of the membrane and tend to bob. up and down between the phospholipid molecules like buoys in a harbor. Some integral proteins penetrate only part way through the bilayer on one side and are monotopic, but most are transmembrane, spanning the membrane all the way from the cytosol to the extracellular fluid.
- Peripheral proteins are completely outside the bilayer. They attach to the projecting ends of integral proteins or to lipid “anchors” sunk in between the phospholipids. Some peripheral proteins face the cytosol, while others face the extracellular fluid.
Classification by Function
In addition to location, cell biologists classify membrane proteins according to their functions as channels, carriers, receptors, enzymes, adhesion proteins, or markers. Read the following descriptions of these proteins and see them illustrated in Figure 6-2.
Figure 6.2: Membrane proteins classified by function
- Channels are tunnel-like transmembrane proteins through which molecules enter or leave the cell. Some channels are always open, like the entrance to a cave. Other channels have door-like “gates” that open and close in response to certain stimuli. Selected molecules move freely through open channels, without the need for energy from ATP. The movement of molecules through channels is similar to water flowing down an open drain.
- Carriers are transmembrane proteins that change shape and, by so doing, move a select- ed molecule across the membrane. Instead of opening a gate to let a substance pass through the membrane by itself, a carrier “escorts” the substance through the membrane. Most organic nutrients, such as glucose and amino acids, move into the cell with the help of carriers. Some carriers require energy from ATP to change shape, but others do not.
- Receptors are integral proteins that act like chemical switches that turn cellular processes on or off. To do this, a specific molecule in the extracellular fluid must attach to a receptor. After the right molecule attaches, the receptor changes shape, triggering chemical reactions within the membrane or cytosol.
- Enzymes are peripheral or integral proteins that catalyze (speed up) chemical reactions. The enzyme’s substrate-binding site faces either the cytosol or the extracellular fluid (but not both). Most membrane enzymes perform hydrolysis reactions that break large molecules into smaller products.
- Adhesion (linker) proteins are integral proteins that bind cells to each other or to other structures in the extracellular fluid. Some adhesion proteins act like tiny “spot welds” that hold cells together. Other adhesion proteins look like thick belts around a cell’s midsection and prevent molecules from slipping between the plasma membranes of adjacent cells. Still other adhesion proteins have channel-like properties that allow molecules to pass directly from one cell into another cell.
- Markers (recognition proteins) are integral proteins with attached oligosaccharides that act like cellular “I.D. tags.” Except for identical twins, the protein markers on a person’s cells are unique to each individual. Protein markers allow a person’s immune system to recognize cells belonging to that person’s body. Without these “self” markers, the immune system would attack the body’s own cells.
MEMBRANE TRANSPORT
Now that you are familiar with the plasma membrane and the organization of the cytoplasm, it is appropriate to describe how the plasma membrane allows the cytoplasm to interact with the extracellular fluid. This section deals with membrane transport, the movement of materials across the plasma membrane. To maintain homeostasis, the plasma membrane must be highly selective in what it allows to pass into and out of the cell; in other words, the plasma membrane must have selective permeability.
Membrane Permeability
The ability of a membrane to allow substances to pass through it is called permeability. A permeable membrane allows substances to pass through it, whereas an impermeable membrane does not. The plasma membrane is permeable to some things but impermeable to others; therefore, it is semipermeable or selectively permeable. Semipermeability allows the plasma membrane to regulate what gets into and out of the cell, much like a border crossing between two countries. Security guards and gates allow certain people and automobiles to cross the border but prohibit others from doing so. Similarly, phospholipids and integral proteins allow only certain types of particles to pass through the plasma membrane.
Note:
While TRICCS can help you remember the functional classification of all proteins (see Chapter 3), use CCREAM to recall the functions of plasma membrane proteins: Channels, Carriers, Receptors, Enzymes, Adhesion proteins, Markers.
Gradients Across a Membrane
The plasma membrane’s selective permeability is directly responsible for differences in the concentrations of various solutes in the cytosol and the extracellular fluid. Any difference in concentration of a substance at two locations is a concentration gradient. Think of this in terms of a highway’s gradient (steepness), in which one section of the highway is higher than another section. Moreover, since ions are charged particles, a difference in their concentrations can cause some regions to become positively charged while other regions become negatively charged.
An electrochemical gradient is a combination of an electrical gradient (difference in electrical charges) and a concentration gradient. Gradients across the plasma membrane can develop in the following ways:
- A substance may pass into and out of the cell at different rates. For example, an active process moves Na+ out of a cell faster than a passive process allows them to enter the cell. This unequal membrane transport creates a higher concentration of Na+ in the extracellular fluid. Likewise, an active process moves potassium ions (K+) into the cell faster than a passive process allows them to leave the cell; consequently, the concentration of K+ is higher in the cytosol than in the ECF.
- The cell may accumulate or deplete a particular substance on one side of the membrane. For example, when oxygen molecules enter a typical cell, the mitochondria utilize them in oxidation reactions. This action causes the cytosol to have a lower concentration of oxygen than the extracellular fluid. In contrast, certain oxidation reactions in the cytoplasm generate carbon dioxide molecules (CO2), causing the cytosol to have a higher CO2 than the extracellular fluid.
As you might expect, the concentration gradient is a major factor in determining whether membrane transport of a particular substance will be passive or active. Passive transport moves substances from regions of higher concentration to regions of lower concentration without consuming cellular energy. Compare this to running out of gas at the top of a hill; you can still coast downhill. Oppositely, active transport can move substances from a region of lower concentration to a region of higher concentration. To move a car uphill, however, the engine must use gas.
Membrane transport can occur by three mechanisms: simple diffusion, protein-mediated transport, and vesicular transport. A fourth mechanism, filtration, relates mostly to the movement of sub- stances between cells.
DIFFUSION
To understand how some kinds of particles move through the plasma membrane, you must first understand why particles move in the first place. At temperatures above absolute zero ( -273o C), molecules and ions vibrate due to the kinetic energy of their subatomic particles. While this vibration causes individual particles to move about randomly, it causes groups of particles to distribute themselves evenly in an environment. The tendency of similar particles to distribute evenly is diffusion (di-FYOO-shun; to scatter).
When particles diffuse, they spread out from a region of higher concentration to a region of lower concentration like a car rolling downhill. For this reason, diffusing substances are said to move down or along their concentration gradient. You can see a dye such as food coloring diffuse through water in a graduated cylinder. The dye molecules spread out from the drop, where they are concentrated, to distribute themselves evenly throughout the water. Although the dye molecules continue to vibrate randomly, diffusion ceases when a concentration gradient no longer exists in the graduated cylinder (see Figure 6-3a).
What would happen if you added two or three different colors of dye to the water at the same time? Interestingly, each solute would diffuse independently of the other solutes but over time, the molecules of each color of dye would distribute themselves evenly throughout the glass of water.
You can also see this happen when a semipermeable membrane separates different solutes (Figure 6-3b). If a solute can pass through the semipermeable membrane, then it is called a permeating solute. Solutes that cannot pass through the membrane are nonpermeating solutes. In the next section we will examine how simple diffusion occurs through the plasma membrane.
Figure 6.3: Diffusion and concentration gradients
Diffusion Through a Cell’s Membrane
Although many different kinds of particles move through the plasma membrane by diffusion, they do not all follow the same route. A substance moves into or out of a cell by diffusion in one of two ways: (1) between the membrane’s phospholipid molecules and (2) through membrane proteins. The route taken by a diffusing substance through the plasma membrane depends on the lipid solubility of the substance.
Lipid-soluble molecules are nonpolar and hydrophobic, which allows them to diffuse through the phospholipid part of the plasma membrane. Examples of substances that diffuse in this manner include molecular oxygen (O2), acids, steroids, fat-soluble vitamins (A, D, E, K), and alcohol. In most tissues, oxygen is in a carbon dioxide (CO2), nitrogen gas (N2), fatty higher concentration in the extracellular fluid; therefore, it diffuses into the cells. Simultaneously, carbon dioxide is in a higher concentration in the cytosol, so it diffuses out of the cell.
Water-soluble substances are polar (hydrophilic) and cannot diffuse between the hydrophobic fatty acid “tails” of the phospholipid bilayer; therefore, these substances must diffuse through integral proteins. Examples of substances that diffuse through integral proteins include ions, glucose, amino acids, and nucleotides. Water molecules are unique in that although they are polar, a few of them can squirt between the phospholipid molecules of the bilayer. Because of their small size and high kinetic energy, water molecules bounce back and forth between the fatty acid tails in the bilayer and eventually reach the other side of the membrane. Any diffusion of a substance through a membrane protein is called facilitated diffusion since the presence of the protein facilitates (makes it easier for) the substance to pass through the membrane.
Most membrane channels are ion channels, which have very small passageways and allow only ions and water molecules to diffuse through them. Furthermore, most ion channels are highly selective, allowing passage for only one kind of ion. Ion channels are classified either leaky or gated.
- Leaky (leak) channels, or pores function like hollow pipes, allowing ions to diffuse through continuously. Examples include leaky sodium (Na+) channels, which allow Na+ ions to diffuse into the cell, and leaky potassium (K+) channels that allow K+ ions to diffuse out of the cell.
- Gated channels have a portion of the integral protein that functions as a “gate.” When the gate closes, no ions diffuse through the channel. When the gate opens, particular ions can diffuse through the channel. The stimuli that open particular gated channels vary. A chemical, generally called a ligand (LIE-gand or LIGG-und; “to bind”) opens a ligand-gated channel. A change in the electrical condition around a cell opens a voltage-gated channel, and a mechanical stimulus, e.g., stretch, opens a mechanically-gated channel, which is also called a stretch-activated channel. Examples of gated channels include ligand-gated Na+ channels, voltage-gated K+ channels, and stretchactivated Ca2+ channels; however, not every type of cell in the body has every type of gated channel mentioned here. Gated channels stay open for only a short moment, closing quickly after the stimulus no longer exists.
While ion channels have names that denote their mode of action and the type of ion diffusing them, water is always the major substance diffusing through them. In addition, most, if not all, cells contain special channels called aquaporins (OK-wa-POR-inz), which are primary routes for the diffusion of water through the plasma membrane.
OSMOSIS: SPECIAL CASE OF DIFFUSION
Now let’s take a closer look at factors affecting the diffusion of water through a plasma membrane. When water diffuses through the plasma membrane or any other semipermeable membrane, the process is called osmosis (oz-MŌ-sis; osmo-, push through; osis, process). During osmosis, water molecules diffuse down their own concentration gradient; that is, from a region with a higher concentration of water molecules to a region with a lower concentration of water molecules. There is an inverse correlation between the concentration of water molecules in a solution and the concentration of solute particles dissolved in the water. In other words, as the concentration of solute particles increases, the concentration of water molecules decreases.
Cells are susceptible to swelling and rupturing if their cytosol has a higher concentration of solute particles than the extracellular fluid. If more water is moving into a cell than is moving out of it, the excess water in the cytosol exerts ever- increasing pressure on the inner face of the plasma membrane. The pressure exerted by water because of its volume, or the effect of gravity is called hydrostatic pressure. In the case of a swelling cell, osmosis is “pulling” water into the cell, while hydrostatic pressure is attempting to push it out. If the hydrostatic pressure inside a cell becomes greater than the plasma membrane can resist, the cell will rupture and die.
To illustrate osmosis and hydrostatic pressure, consider an aquarium divided into two chambers (A and B) by a partition that has a semipermeable membrane at the bottom (see Figure 6-4). If we add distilled water (contains no solutes) to both sides, then both sides have the same concentration of water per unit volume. If we add a solute, such as salt or sugar, to side B, then side B will have fewer water molecules per unit of volume compared to the distilled water because the solute particles take up space that was formerly occupied by water molecules. Due to osmosis, there will be a net movement of water from side A to side B. Water will move from the side with more water molecules per unit of volume (A) to the side with fewer water molecules per unit of volume (B), causing the water level on side B to rise.
Figure 6.4: Osmotic and hydrostatic pressure
Osmolarity (OZ-mō-LAR-i-tē) is a measure of the concentration of solute particles in a solution, and it allows you to predict whether water will move into or out of a cell by osmosis. The standard units for osmolarity are milliosmoles of solute per liter of solution (written mOsm/L). Normal human tissue fluid usually contains a solute concentration of 300 mOsm/L. When comparing two solutions separated by a with the higher concentration of solute particles has a higher osmolarity. In our aquarium example, B has a higher osmolarity than side A after we add solute to side B. Water always moves through a semipermeable membrane from a region of lower osmolarity (higher water concentration) toward a region of higher osmolarity (lower water concentration). The tendency of a solution to gain water because of its osmolarity is osmotic pressure. In the figure, side B shows a greater tendency to gain water than does side A; therefore, side B has a higher osmotic pressure than side A. More exactly, osmotic pressure is the force required to prevent osmosis. You could determine the osmotic pressure of solution B by measuring the amount of pressure exerted by a piston that prevents a net movement of water into side B.
When predicting how extracellular fluid will affect a cell’s volume, or internal tension, it is common to use the term tonicity (tō-NI-si-tē; tonic, strength) instead of osmolarity. A solution’s tonicity relates to its concentration of nonpermeating solutes. An isotonic (Ī-sō-TON- ik; iso, same) solution has the same concentration of nonpermeating solute particles as the cell’s cytosol. A 0.9% NaCl solution, which is approximately 300 mOsm/L, is isotonic to human cells because it does not cause the cells to lose or gain water. A hypertonic (hyper, high) solution has a higher concentration of nonpermeating solute than a cell and causes the cell to lose water. Cells that are losing water may often notched). A hypotonic (hypo-, low) solution has a lower concentration of nonpermeating solute particles than the cell and causes the cell to gain water and swell. In some cases, such as with red blood cells, a hypotonic solution can cause the cells to swell so much that they rupture: a phenomenon called lysis (LĪ-sis, loosening).
When considering how different solutes affect a solution’s osmotic pressure, the number of particles is more important than the type of particles. In general, one small solute particle has the same effect on osmotic pressure as a larger solute particle. For example, although a single ion may be small, its strong electrical charge attracts numerous water molecules that form hydration shells around the ion. A polar molecule also attracts water molecules, but the attraction is only around the charged regions of the molecule. Therefore, a small ion with a “larger” hydration shell may tie up as many water molecules as a larger polar molecule with its “smaller” hydration shells (see Figure 6-5).
Figure 6.5: Hydration shells
Figure 6.6: Effect of different solutes on osmolarity
Although a 0.9% NaCl solution is isotonic to a human cell, it takes a 5% glucose (dextrose) solution to be isotonic to the same cell. Why does it take a little more than five times as much weight of glucose dissolved in water to make an iso-osmotic solution compared to a 0.9% NaCl solution? The reason is that when one glucose molecule (C6H12O6) dissolves in water (when surrounded by polar water molecules), it does not ionize. In contrast, when one NaCl dissolves, it ionizes to form one Na+ ion and one Cl– ion. We will use Figure 6-6 to illustrate this idea but read its explanation below.
Explanation of Figure 6-6
The top left corner of the figure shows that 1 gram of substance A dissolves to yield eight “small” solute particles. Think of this as being like Na+ and Cl- dissolving out of a salt crystal. The top right corner shows that 1 gm of substance B dissolves to form two “large” solute particles. Think of this as being like glucose molecules dissolving out of a sugar crystal. Notice that compartments 1 and 2 both contain 8 solute particles per 100 mL of solution. However, compartment 2 contains 4 grams of substance B, while compartment 1 contains only 1 gram of substance A. Still, the number of solute particles in compartments 1 and 2 are the same; hence, they are iso-osmotic (i.e., they have the same osmotic pressure). Compartment 3 shows a mixture of substances A and B, but the concentration is 10 particles per 100 mL, which makes it hyperosmotic to compartments 1 and 2. Compartment 4 contains a variety of solutes, including A and B, but the total number of solutes per 100 mL is still 8; therefore, it is iso-osmotic to compartments 1 and 2, and it is hypoosmotic to compartment 3.
Although a 5% glucose solution is initially isotonic to a human cell, it can become hypotonic because glucose is a permeating solute; that is, a cell may readily absorb it, thus, decreasing the solute concentration in the solution. Remember that NaCl is a nonpermeating solute because cells do not allow it to pass through the plasma membrane readily. Therefore, a 0.9% NaCl will remain isotonic to a living cell, whereas a 5% glucose solution is initially isotonic but becomes hypotonic when glucose molecules enter the cell. Figure 6-7 shows the effects that different solutions have on the osmotic pressure around a red blood cell. Remember, NaCl is a nonpermeating solute and glucose is a permeating solute.
Dialysis
Dialysis (dī-AL-i-sis; to separate) is a passive process involving the separation of different- size solute particles using a semipermeable membrane. Only smaller solute particles can pass through the membrane. Dialysis is used in artificial kidneys to cleanse the blood of patients whose kidneys no longer function efficiently. In Figure 6-8, some of the solutes are able to pass through the semipermeable membrane, while others are prevented; this is an example of dialysis. Notice in the figure how dialysis can also affect osmosis.
FACTORS AFFECTING DIFFUSION
Now consider factors that affect how fast diffusion occurs. This is important because if diffusion of nutrients into a cell or the diffusion of wastes out of a cell is too slow, the cell can suffer ill effects. The rate, or speed, of diffusion fluctuates in response to three major factors.
- Temperature: When molecules and ions are warmer, their subatomic particles have more kinetic energy and vibrate faster. This, in turn, causes molecules and ions to diffuse faster through the plasma membrane. Moreover, warmer molecules within the plasma membrane vibrate faster and can “bump” diffusing substances through at a faster rate.
- Molecule size: Large particles have more surface area than smaller particles and are more likely to bump into other particles while diffusing. Consequently, larger particles encounter more resistance and diffuse more slowly than smaller particles under the same conditions. Think of scooters darting quickly between slow-moving cars in rush-hour traffic.
- Steepness of the gradient: The greater the difference in concentration of a substance at two locations, the steeper the concentration gradient. In turn, the steeper the concentration gradient for a particular substance, the faster that substance will diffuse. As a comparison, a car will roll down a steep hill much faster than it will roll down a gentle (less steep) slope. Likewise, a greater difference in electrical charge at two locations (that is, the greater the electrochemical gradient), the faster ions will diffuse to regions of opposite charge.
Figure 6.7: Effect of permeating and nonpermeating solutes on RBCs
Figure 6.8: Dialysis
CARRIER-MEDIATED TRANSPORT
Some substances enter or leave a cell without passing through the phospholipid bilayer or membrane channels. These substances are either (1) too large to pass through a channel, or (2) they must move against a concentration gradient. Most of these substances, called substrates, move through integral proteins called carriers in a process called carrier-mediated transport. There are two methods of carrier-mediated transport: facilitated transport and active transport.
Facilitated Transport
If a substrate can move through a carrier that does not require the cell to use ATP as a source of energy, the process is facilitated transport. The name implies that the carrier helps the movement of the substrate. When the substrate moves down a concentration gradient, facilitated transport is synonymous with facilitated diffusion. However, research has shown that facilitated transport can move a substrate through the membrane even when there is no concentration gradient. In either case, the cell does not use up energy to make this happen, so facilitated transport is a passive process.
To see how facilitated transport helps maintain homeostasis, consider the movement of glucose into and out of liver cells through the same carriers. When blood has a higher concentration of glucose than the liver cells, glucose enters the cells by facilitated transport. When the liver cells have a higher concentration of glucose than the blood, glucose leaves the cells by facilitated transport. In this way, facilitated transport helps maintain a relatively stable concentration of glucose in the blood. The steps in facilitated transport are as follows and are shown in see Figure 6-9a:
- Substrate binds to receptor: The substrate binds to a site, called a receptor, located on the carrier. The binding is specific; only a certain kind of substrate can bind to the receptor, like a key fitting into a lock. Both sides of the carrier display receptors, thus, substrate molecules in the ECF or in the cytosol can attach to the carrier. However, the side with the higher concentration of substrate will bind more substrate molecules. As a result, there will be a net movement of the substrate down its concentration gradient.
- Carrier changes shape: Binding of the substrate causes the carrier to change shape, and this action moves the substrate across the membrane. Notice the substrate is moving down its concentration gradient and no ATP energy is required to change the carrier’s shape.
- Substrate detaches from receptor: After moving down its concentration gradient through the carrier, the substrate detaches from the carrier and diffuses away from it. Since this side of the membrane has a relatively low concentration of substrate, it is unlikely that a substrate particle will be available to bind to the receptor on that side.
- Carrier changes shape: After the substrate detaches, the carrier changes shape so the receptor returns to the side of the membrane with the higher concentration of substrate. Another substrate molecule attaches to the receptor and facilitated transport occurs. The speed at which substrate particles move down their concentration gradient by facilitated transport is directly proportional to the steepness of the gradient. In other words, the greater the difference in concentration of substrate on either side of the membrane, the faster facilitated transport occurs. If the concentration of substrate is the same on either side of the membrane, facilitated transport still occurs, but in both directions at the same rate.
Figure 6.9: Facilitated diffusion and saturation point
Although carriers can transport many substrate particles each second, they can only work so fast. The maximum number of substrate molecules that can pass through a carrier in a given amount of time is the carrier’s saturation point (see Figure 6-9b). Compare this to the maximum number of people who can ride an escalator from the second floor to the first floor of a building each minute. Regardless of how many people are waiting on the second floor, no more than a maximum number can ride the escalator each minute. Can you see why our analogy needs to have people riding down the escalator? Facilitated transport will always be down a concentration gradient.
Active transport
While facilitated transport moves a substrate down a concentration gradient, active transport moves a substrate against a concentration gradient. In the same way that a car must burn fuel to move uphill, a cell must expend energy to move a substance from a region of low concentration into a region of higher concentration. Active transport helps maintain optimum concentrations of various solutes inside and outside of the cell, which is crucial to maintaining homeostasis. Like facilitated transport carriers, active transport carriers change shape to transport substrates across the membrane. Also, like the facilitated diffusion carrier, an active transport carrier can experience saturation. However, in our analogy, the people would be riding the escalator up to the second floor. Depending on whether the carrier expends cellular energy directly or indirectly, active transport is either primary or secondary, respectively.
Primary active transport uses energy derived from ATP molecules to change a carrier’s shape in order to move a substrate across a membrane against a concentration gradient. Although there are variations, the general process occurs in three steps. First, a substrate attaches to a receptor site on the carrier. Second, an ATP molecule transfers one of its phosphate molecules to the carrier. In response, the carrier changes shape, allowing it to move the substrate across the membrane. Third, the carrier releases the substrate and the phosphate molecule. Losing the phosphate causes the carrier to change back to its original shape and the process repeats.
Active transport carriers function as mem- brane pumps, implying that they require energy to “push” a substrate against a concentration gradient. Compare this to a water pump that uses electrical energy to push water uphill because the water will not move “up” under its own power. The plasma membrane has a variety of pumps, but one of the most important is the sodium-potassium (Na+/K+) pump. Recall that Na+ ions diffuse into the cell and potassium ions diffuse out of the cell through leaky channels. To counteract this diffusion, the Na+/K+ pumps move Na+ ions out of the cell and move K+ ions into the cell. Without Na+/K+ pumps are so important to all cells in the body, we will describe their activity. Identify the following steps in Figure 6-10:
- Sodium ions attach to pump: Three Na+ ions in the cytosol bind to receptors on the cytosolic side of the pump. At this time, the pump cannot bind K+</sup. ions.
- ATP phosphorylates the pump: ATP transfers a phosphate group (PO4 3-) to the pump. This step can occur only if the pump is holding three Na+ ions.
- Pump changes shape: Phosphorylation causes the pump to change shape, in essence, turning “inside out” so that the Na+ ions now face the extracellular fluid.
- Pump releases Na+ ions and bind K+ ions: The three Na+ ions detach from the pump and enter the extracellular fluid. When this happens, the receptor sites for Na+ change shape, preventing Na+ ions from binding to the pump. At the same time, the receptor sites for K+ ions become available, allowing two K+ ions to enter the pump from the extracellular fluid.
- PO4 3- detaches from the pump: When the K+ ions bind to the pump, the pump changes shape slightly, which, in turn, causes the PO3 4- group to detach from the pump and enter the cytosol.
- Pump releases K+: Detaching the PO4 3- group causes the pump to change shape again, virtually turning “outside in” so that the K+ ions now face the cytosol. The K+ ions quickly detach from the pump and enter the cytosol. The pump is now ready to accept three Na+ ions, and repeat steps 1-6.
Figure 6.10: The sodium-potassium pump
Two other examples of primary active transport carriers are calcium pumps and chloride pumps. Calcium pumps transport Ca2+ ions out of cells, maintaining a lower concentration of Ca2+ in the cytosol than in the ECF. Chloride pumps transport Cl– ions out of the cell, maintaining a lower concentration of Cl– ions in the cytosol than in the ECF. Although the cell must expend energy to maintain ion concentration gradients across membranes, these ions may diffuse back through the membranes and perform useful work for the cell. This energy tradeoff is like using an electric pump to push (“actively” transport) water into a tall tower so that later the water can flow passively down a pipe and through a showerhead, allowing you to take a shower. Like facilitated transport carriers, active transport pumps have a saturation point at which they cannot work any faster.
Secondary active transport uses the kinetic energy released during facilitated transport of one substance to move another substrate through the same carrier protein. During this process, a single carrier binds several substrates and transports them through the membrane simultaneously. One of these substrates always moves down its concentration gradient (passive transport), while the other substrate may move either along or against a concentration gradient. Most secondary active transport carriers have receptor sites for two different substrates, and both substrates must bind to the carrier before the carrier will change shape and transport them through the membrane.
A secondary active transport carrier does not derive energy from ATP directly; instead, it derives kinetic energy from the movement of one of its substrates down a steep concentration gradient. This kinetic energy is the “driving force” that moves the other substrate through the carrier against a concentration gradient. Most often, a Na+ ion is the substrate that moves down its concentration gradient through a secondary active transport carrier. Since Na+ ions are in a higher concentration in the ECF, they always move through a secondary carrier into the cytosol. Without a steep concentration gradient to promote the binding of Na+ ions to its outside surface, a secondary carrier loses its source of kinetic energy. Consequently, these secondary carriers rely on Na+/K+ pumps, which do utilize energy from ATP directly, to maintain a steep concentration gradient for Na+ across the membrane. In this way, secondary active transport derives energy indirectly from primary (“first”) active transport.
Secondary active transport carriers are coupled transporters because they couple the transport of one substrate to the transport of another substrate. A coupled transporter is either a symporter or an antiporter. A symporter transports different substrates simultaneously in the same direction in a process called cotransport. Some symporters cotransport amino acids into a cell in conjunction with Na+ ions. An antiporter transports different substrates simultaneously in opposite directions spatially in a process called countertransport. One type of antiporter transports H+ ions out of the cell while transporting Na+ ions into the cell. In this case, the H+ ions are moving against their gradient but Na+ are moving along their gradient. The Na+ are moving into the cell via facilitated diffusion. Since the H+ ions are byproducts of normal metabolism, this antiporter prevents them from accumulating in the cytosol and lowering its pH. Figure 6-11 illustrates primary and secondary active transport.
Figure 6.11: Primary and secondary active transport
BULK (VESICULAR) TRANSPORT
In certain situations, it is important for a cell to take in, or get rid of, substances that are too large to pass through the plasma membrane’s lipid bilayer, its channels, or its carriers. These substances can enter or leave a cell by hitching rides inside of vesicles in a process called bulk (vesicular) transport. Recall, a vesicle is a spherical, membranous sac that forms when a portion of an existing membrane pinches off. Some vesicles form at certain cytoplasmic organelles, while others form at the plasma membrane. Since vesicles arise from membranes, they can also fuse with them.
A cell uses its cytoskeleton to organize phospholipid molecules into a vesicle. To begin forming a vesicle, motor molecules pull on cytoskeleton microfilaments that are anchored to an existing membrane. Eventually, the microfilaments pull a small portion of the membrane off as a vesicle. While it is forming, a vesicle surrounds a substance that is waiting for transport. A motor molecule then binds to the vesicle and carries it along a microfilament. Since the motor molecules need ATP to form and transport the vesicles, bulk transport is an active process. The two major types of bulk transport are endocytosis and exocytosis.
Endocytosis
When a cell is ready to move a relatively large substance from the extracellular fluid to the cytosol, it performs a process called endocytosis (en-dō-sī-TŌ-sis; endo, inside). Endocytosis occurs in three ways: phagocytosis, pinocytosis, and receptor–mediated endocytosis.
Phagocytosis (fā-gō-sī-TŌ-sis; phag, to eat) is a type of endocytosis in which a cell ingests relatively large, solid particles. These particles may include dead or dying body cells, cellular debris, bacteria, viruses, or some other solid object. The cell first extends pseudopodia (projections of its plasma membrane) around the particle completely enveloping it. The pseudopodia come together to form an endocytic vesicle (EN-dō-SI-tik) called a phagosome (FĀ-go-sōm); see Figure 6-12.
Figure 6.12: Bulk transport
The body uses cells called phagocytic cells, or phagocytes, as a defense against foreign particles. Phagocytes in the body are certain types of white blood cells. The type that has the most voracious appetite for bacteria and viruses is the macrophage (MAK-rō-fāj). A macrophage develops from a certain type of white blood cell that leaves the blood to move around in other tissues. In a sense, macrophages are like police officers who walk the streets looking for troublemakers; in most cases, the troublemakers are bacteria or viruses. Macrophages also use phagocytosis to clean up wounds by ingesting dead body cells.
Before a macrophage can ingest a particle by phagocytosis, there must be a receptor on the particle’s surface for the macrophage to grab. Often the receptor is a chemical that attaches to the particle shortly after the particle enters the body. After phagocytosis, a motor molecule pulls the phagosome through the cytosol where it fuses with a lysosome. Digestive enzymes from the lysosome break down the contents of the phagosome into a variety of chemical products. The usable products enter the cytosol where the cell can use them for energy or for cellular components. The cell expels the unusable material through exocytosis, described shortly.
Pinocytosis (pin-ō-sī-TŌ-sis; pino, to drink) is a type of endocytosis in which a cell ingests a small amount of extracellular fluid. Unlike phagocytosis, pinocytosis does not use pseudopodia, and it does not require recognition of receptors. Instead, the plasma membrane simply pulls inward and traps a small amount of extracellular fluid within an endocytic vesicle. Pinocytosis occurs continually and is the cell’s way of “sampling” its surrounding environment. Various solutes leave the endocytic vesicle as it moves through the cytosol. A broader benefit of pinocytosis is that it allows cells in the intestines to absorb a variety of dissolved nutrients from food.
Receptor-mediated endocytosis forms a vesicle only after a substrate binds to a receptor (mostly glycoproteins) on the plasma membrane. Substrates ingested by this method include cholesterol, iron, and certain hormones and vitamins. Certain types of white blood cells use receptor- mediated endocytosis to ingest foreign particles that can cause illness. The receptors on the surface of these white blood cells are special proteins called antibodies. An antibody is highly specific in that it will bind only to one type of foreign particle. Receptor-mediated endocytosis (RME) is similar to pinocytosis in that there are no pseudo- podia; the plasma membrane simply pulls inward to form a vesicle. However, there are three major differences between RME and pinocytosis. (1) Whereas pinocytosis occurs continually, RME oc- curs only when a certain substrate is present in the extracellular fluid. (2) Whereas pinocytosis is nonspecific and takes in whatever dissolves in the extracellular fluid, RME is highly specific, taking in only a certain type of particle. (3) Whereas pinocytosis makes vesicles that have the same concentration of particles as the extracellular fluid, RME makes vesicles that have a much higher con- centration of particles than the extracellular fluid. Now consider a specific example of receptor- mediated endocytosis, one in which a cell absorbs cholesterol for its plasma membrane. Hundreds of cholesterol molecules move together in the blood, surrounded by a shell of phospholipids and protein. This lipid-protein mass is a lipoprotein. Different lipoproteins have different molecular weights, but the type mainly responsible for transporting cholesterol is a low-density lipoprotein, or LDL. The method by which a cell absorbs and processes an LDL involves the following steps (see Figure 6-13):
Figure 6.13: Receptor-mediated endocytosis
- Binding of LDL to receptor: A protein on the LDL binds to an LDL receptor on the outer surface of the plasma membrane.
- Migration to a coated pit: The membrane receptor with its bound LDL moves along the plasma membrane until it reaches a small depression called a coated pit. Clathrin (KLĀ-thrin; lattice) is a protein that forms a net-like lining along the cytoplasmic side of this pit. Moving more receptors with bound LDLs into the pit concentrates the LDLs in one place.
- Formation of a vesicle: Myosin motor molecules pull microfilaments that connect to the clathrin-coated pit, causing the pit to bow inward and form a vesicle. Shortly thereafter, the clathrin molecules detach from the vesicle and return to the cell membrane. A motor molecule attaches to the vesicle and pulls it farther into the cytosol along microfilaments of the cytoskeleton.
- Separation of LDL and receptor: The receptors and their LDLs separate from one another and the vesicle splits in two. The receptors end up in one vesicle and the LDLs in the other vesicle.
- Migration of vesicles: The vesicle containing the LDL receptors migrates back to the plasma membrane and fuses with it. This causes the receptors to end up on the outer surface of the membrane. The vesicle containing the LDL fuses with a lysosome. Enzymes break up the LDLs and release the cholesterol molecules, which move to the cell membrane and become integrated within it. Amino acids from the protein to which the cholesterol was bound are recycled in the cell.
Exocytosis
The opposite of endocytosis is exocytosis (ex- ō-sī-TŌ-sis; exo, outside). During this process, a secretory vesicle releases its contents into the extracellular fluid after fusing with the plasma membrane (refer back to Figure 6-11). In addition, the phospholipids that make up the vesicle become part of the plasma membrane, which causes the membrane to grow. Since endocytosis removes part of the plasma membrane, if a cell is to maintain a constant size, the amount of exocytosis and endocytosis must be equal.
The cell uses exocytosis to secrete a variety of substances into the extracellular fluid. The se- cretory vesicles move along microfilaments and finally turn inside out when they fuse with the plasma membrane. This ensures that the vesicle releases its contents to the outside of the cell. The cell also uses exocytosis to rid itself of waste products that are too large to pass through channels or carriers. For example, after a lysosome breaks down solid particles inside other vesicles, it expels the indigestible pieces from the cell by exocytosis.
CELL SIGNALING
Now, we turn our attention to cell signaling, which includes methods cells use to communicate with each other. This is important because homeostasis requires coordinated interactions among different cells in the body, and the ways cells communicate may vary. There are two methods by which cell communication might occur through direct contact between adjacent cells. One example is when chemicals can pass from the cytoplasm of one cell directly into the cytoplasm of an adjacent cell through small, tunnel-like channels called gap junctions. These channels are made of transmembrane proteins called connexons (kuh-NEX-onz); see Figure 6-14a.
In another example, a receptor protein on the surface of one cell can recognize and bind to a marker protein on the surface of another cell, allowing the cells to “recognize” one another. This is important for the body’s defense against foreign particles that can cause disease; see Figure 6-14b. Most cell communication, however, employs chemicals released into the extracellular fluid; these chemicals are called extracellular messengers (ECMs). The cell that releases an ECM is called the secretory cell (SEE-krih-tor-ee), and the ECM is a secretion (see-KRE-shun; “to separate”). Note the word “secretion” is also a verb that refers to the release of the secretion. The cell affected by the ECM is called the target cell.
Figure 6.14: Cell communication through direct contact
Classification ECMs
Not all extracellular messengers are the same, so it is helpful to compare them based on their differences. We can classify any ECM based on two criteria: distance to target and solubility.
ECMs Classified by Distance to Target
Based on distance to the target cell, ECMs are autocrine, paracrine, and/or endocrine. An ECM is autocrine (AW-to-krin; auto, self; crine, secretion) if the secretory cell is also the target cell. The ECM is paracrine (para-, alongside) if the target cell is nearby. One type of paracrine secretion is a neurotransmitter, a chemical released from a neuron into a small gap, called a synapse, located between the neuron and an adjacent cell. Paracrine secretions from other secretory cells may be referred to as local mediators, factors, or agents. The ECM is an endocrine secretion (“inside secretion”) if it travels in blood to reach target cells farther away. More specifically, endocrine secretions are called hormones.
ECMs Classified by Solubility
ECMs are either lipophilic or hydrophilic. Lipophilic (“fat-loving”) ECMs are soluble in polar solvents, but they are not soluble in water. This is because they are nonpolar and, therefore, have no part around which water hydration shells can form. For this reason, lipophilic molecules are hydrophobic (“water-fearing”). Most lipophilic hormones travel in the blood “bound” to another chemical, typically a protein, which can allow them to stay more evenly dispersed in the blood’s watery plasma. In contrast, hydrophilic (“water-loving”) ECMs are soluble in water because they are polar, and hydration shells readily form around them in a watery environment. Being hydrophilic allows these ECMs to travel in the blood “unbound,” that is by themselves and not bound to another chemical. Hydrophilic ECMs can also be classified as lipophobic (“fat-fearing”) since they do not mix well with lipids.
Classification ECM Receptors
When an ECM reaches its target cell, before it can cause an effect, it must bind to a specific protein called a receptor. Binding of the ECM can activate the receptor by causing it to change shape. The activated receptor, in turn, can initiate changes inside the target cell. ECM receptors are classified in two ways: location and effect of their activation in the target cell.
Classification by Location
Based on their location in the target cell, ECM receptors are either intracellular or membrane bound.
Intracellular receptors are inside the target cell and are utilized by lipophilic ECMs that can pass directly through the phospholipid plasma membrane. Some lipophilic ECMs bind to receptors that cause reactions in the cytoplasm, while others bind to receptors that affect genes in the nucleus.
An example of a lipophilic ECM that binds to cytoplasmic receptors but does not enter the nucleus is nitric oxide (NO), which is released from cells lining the inside of blood vessels. The NO from the secretory cell enters a nearby smooth muscle cell in the blood vessel wall and binds to a receptor that has an enzyme component called guanylyl cyclase. Binding NO to the receptor causes the cyclase to convert GTP (guanosine triphosphate) to cGMP (cyclic guanosine monophosphate). See the relevance of cyclase in the enzyme’s name? The cGMP then activates a kinase enzyme that, in turn, phosphorylates another kinase, called MLCK (myosin light-chain kinase). An active MLCK is needed for smooth muscle contraction, but this phosphorylation deactivates the MLCK and causes the muscle to relax. The result of the smooth muscle relaxation in the vessel wall causes the vessel to open up, and this is called vasodilation (VA-zo-die-LAY-shun; “vessel widening”). The NO intracellular pathway is shown in Figure 6-15.
Figure 6.15: Lipophilic nitric oxide pathway for vasodilation
Intracellular receptors that affect genes in the nucleus are called nuclear receptors and they are classified as either type I or type II. Type I nuclear receptors are found in the cytoplasm, but after binding with the ECM will enter the nucleus where they either activate or deactivate specific genes. Steroidal hormones, including sex hormones and corticosteroids, bind to type I receptors. Type II nuclear receptors are already in the nucleus, making them intranuclear, so the ECM must pass through the cytoplasm and also the nuclear membrane before binding to the receptor in the nucleus. Thyroxine, a lipophilic hormone released from the thyroid gland in the neck region, binds to a type II receptor. Figure 6-16 compares the two types of nuclear receptors.
Figure 6.16: Types of nuclear receptors
Membrane-bound receptors are part of the target cell’s plasma membrane. Since hydrophilic ECMs cannot pass through the phospholipid bilayer membrane of the target cell, they must attach to membrane-bound receptors to cause an effect.
Receptors Classified by Effect
Based on the effect of their activation, ECM receptors may be ionotropic, metabotropic, or nuclear. Ionotropic receptors (eye-ON-oh-tropik) are ligand-gated, transmembrane ion channels; therefore, they are membrane-bound receptors. When the ECM (ligand) attaches to the channel, it opens and allows ions (charged particles) to move either into or out of the cell. As we will describe in a later chapter, moving charged particles through the membrane can affect the electrical condition around the membrane. Metabotropic receptors (meh-TABoh- tro-pik) affect an aspect of the target cell’s metabolism, either increasing or decreasing it. Nuclear receptors bind to DNA in the nucleus and either promote or inhibit transcription of genes. All nuclear receptors are intracellular.
Signal Transduction
The series of steps through which ECMs cause changes (responses) in target cells is called signal transduction. Signal transduction for most lipophilic ECMs results in gene regulation, which can have wide ranging effects since it ultimately influences the types and amount of protein synthesized in the cell. Recall that lipophilic ECMs utilize intracellular receptors, classified as either type I or type II (see Figure 6- 15). In contrast, signal transduction for hydrophilic ECMs involve membrane-bound receptors, i.e., they are part of the target cell’s plasma membrane. There are three main types of membrane-bound receptors: enzyme, enzyme-coupled, and G protein-coupled.
Enzyme Receptors
An enzyme receptor is a transmembrane protein that functions as an enzyme after the ECM binds to it. ANP (atrial natriuretic peptide), a hormone from the heart that helps decrease blood pressure, binds to a cyclase receptor. This enzyme converts GTP to cAMP, which then activates a kinase enzyme. As seen with nitric oxide earlier, the active kinase phosphorylates proteins that affect the cell in some way. On the other hand, insulin, a pancreatic hormone that helps most body cells absorb glucose for energy, binds to a kinase receptor, activating it in the process. The kinase phosphorylates an inactive relay protein, which then becomes active and can affect various metabolism pathways. Figure 6-17 shows the cyclase and kinase pathways.
Figure 6.17: Enzyme receptors
Enzyme-Coupled Receptors
An enzyme-coupled receptor is a transmembrane protein that does not function directly as an enzyme but is connected (coupled) to an enzyme attached to the inside border of the membrane. One of the most commonly used membrane-bound enzymes is janus kinase (JAK), so-named for its double-protein structure being like the two-faced Roman god, Janus. Binding the ECM to the receptor allows the JAK protein to phosphorylate, and thereby activate, a cytosolic protein called STAT (signal transducer and activator of transcription). As its name implies, the active STAT protein can enter the nucleus and promote transcription of specific genes. Hormones that use the JAK-coupled receptor pathway includes growth hormone, prolactin, which promotes milk production, and erythropoietin (EPO), which promotes red blood cell formation. Figure 6-18 shows signal transductions using the JAK protein.
Figure 6.18: Enzyme-coupled receptors
G Protein-Coupled Receptors
The G protein-coupled receptor is a transmembrane protein that is coupled to a G protein, so-named because it binds to GDP and GTP. The G protein has three subunits: alpha, beta, and gamma. Before the ECM binds to the receptor, the alpha subunit is bound to GDP, but after the ECM binds to the receptor, the alpha subunit exchanges the GDP for GTP. The alpha subunit then detaches from the other two subunits the G protein and moves to a target protein located nearby on the cytosolic side of the plasma membrane. The GTP transfers its third phosphate to the target protein, but the GDP remains attached to the alpha subunit, which then returns to the G protein. If the phosphorylated (activated) target protein is an ion channel, it can affect ion movement into or out of the cell. If the target protein is an enzyme, it can generate a second messenger molecule that can initiate reactions inside the cell. In these cases, the ECM is called the first messenger. Examples of second messengers include cAMP, IP3, DAG, and Ca2+ ions.
- cAMP as a Second Messenger: When some ECMs activate G protein-coupled receptors on the target cell’s plasma membrane, the receptor activates a membrane-bound enzyme called adenylate cyclase (also called adenylyl cyclase). The activated cyclase dephosphorylates ATP to form cAMP (cyclic adenosine monophosphate), which, in turn, activates a kinase enzyme in the cytoplasm. The cAMP functions as a second messenger by affecting other cytoplasmic proteins to cause an effect. In other cases, the activated G protein inhibits the adenylate cyclase, so the cAMP does not form. See the formation of cAMP in Figure 6-19.
Figure 6.19: cAMP second messenger pathway
- IP3, DAG, and Ca2+ as Second Messengers: Some ECMs bind to G protein-coupled receptors that activate (or deactivate) a membrane-bound enzyme other than adenylate cyclase, namely phospholipase C. This enzyme is named for its ability to convert phospholipid molecules from the target cell’s plasma membrane to second messengers, including IP3 (inositol triphosphate) and DAG (diacylglycerol). The IP3 opens channels in the endoplasmic reticulum, causing the release of stored Ca2+ ions, also considered second messengers. The Ca2+ ions, along with the DAG, activate kinase enzymes that phosphorylate other cytoplasmic proteins to cause an effect. Figure 6-20 shows the formation of these other second messengers.
Figure 6.20: IP3, DAG, and Ca2+ second messenger pathway
Signal Amplification and Termination
While ECMs can dramatically affect activities in their target cells, it is important to keep those activities under control. What is more, only a few ECM molecules are required to cause significant effects on the target cell. This is due to a phenomenon called signal amplification, in which one ECM molecule can initiate a reaction that leads to another reaction, and another, and so on. This is called a cascade effect. Amazingly, one ECM molecule may ultimately cause the activation of over 100,000 effector proteins.
When it is necessary to pull back on the effects an ECM is having on the target cell, mechanisms are in place to do so, and this phenomenon is called signal termination. There are four general ways signal termination may occur. First, enzymes can hydrolyze the ECM, preventing it from continually activating its receptor. Second, in the case of hydrophilic ECMs, organic second messengers can be activated by phosphodiesterase enzymes. Third, when Ca2+ ions are the second messengers, they can be pumped back into the endoplasmic reticulum. Fourth, in cases where phosphorylation caused activation of effector molecules, phosphatase enzymes in the cytosol can dephosphorylate and, thereby, deactivate them. In future chapters, we will learn more about specific ECMs associated with various organ systems and how those ECMs have their effects.
Flashcards
Master the Cell Membrane & Transport
Glossary
Key terminology for the cell membrane and transport, including types of transport, membrane structure, and cell communication. Click on any term to see its definition.
