Chapter Fifteen

Local signals book, or chemicals that bathe a cell, such as lactose in the medium surrounding E. coli. It may come from outside the organism, such as the scent of a female moth seeking a mate in the dark, or from a neighboring cell within the organism, as in the heart, where thousands of muscle cells contract in unison by transmitting signals to one another.

Of course, the mere presence of a signal does not mean that a cell will respond to it, just as you do not pay close attention to every sound in your environment as you study. To respond, the cell must have a specific receptor protein that can bind to the signal. In the following section, we will describe some of the signals different cells respond to and look at one model signal transduction pathway. After discussing signals, we will consider their receptors.

Cells receive signals from the physical environment and from other cells

The physical environment is full of signals. Our sense organs allow us to respond to light, odors and tastes (chemical signals), temperature, touch, and sound. Bacteria and protists respond to even minute chemical changes in their environment. Plants respond to light as a signal. For example, at sunset, at night, or in the shade, not only the amount , but also the wavelengths of the light reaching Earth's surface differ from that of full sunlight in the daytime. These variations act as signals that affect plant growth and reproduction. Some plants also respond to temperature: when the weather gets cold, they respond either by becoming tolerant to cold or by accelerating flowering. Even magnetism can be a signal: some bacteria and birds orient themselves to Earth's magnetic poles, like a needle on a compass.

A cell inside a large multicellular organism is far away from the exterior environment. Instead, its environment consists of other cells and extracellular fluids. Cells receive their nutrients from, and pass their wastes into, extracellular fluids or gases. Cells also receive signals—mostly chemical signals—from their extracellular fluid environment. Most of these chemical signals come from other cells. Cells also respond to chemical signals coming from the environment via the digestive and respiratory systems. And cells can respond to the concentrations of certain chemicals, such as CO2 and H+, whose presence in the extracellular fluids results from the metabolic activities of other cells.

Inside a large multicellular organism, chemical signals reach a target cell by local diffusion or by circulation within the blood. Autocrine signals are signals that affect the cells that make them. Paracrine signals are signals that diffuse to and affect nearby cells. Signals to distant cells, such as hormones, usually travel through the circulatory system (Figure 15.1).

In all cases, the cell must be able to receive or sense the signal and respond to it. Depending on the cell and the signal,

Autocrine signals bind to receptors on the cells that secrete them.

Autocrine signals bind to receptors on the cells that secrete them.

Distant signals

Paracrine signals bind to receptors on nearby cells. _

^Receptor fY)

Cells without receptors do not respond to a particular signal.

Distant signals

Circulating signals are transported by the circulatory system and bind to receptors on distant cells.

Circulating signals are transported by the circulatory system and bind to receptors on distant cells.

Secreting cell

Circulatory vessel (e.g., a blood vessel)

15.1 Chemical Signaling Systems A signal molecule can act on the cell that produces it, or on a nearby cell. Many signals act on distant cells, to which they are transported by the organism's circulatory system.

Secreting cell

Circulatory vessel (e.g., a blood vessel)

Target cell

15.1 Chemical Signaling Systems A signal molecule can act on the cell that produces it, or on a nearby cell. Many signals act on distant cells, to which they are transported by the organism's circulatory system.

the responses range from entering the cell division cycle to heal a wound, to moving to a new location in the embryo to form a tissue, to releasing enzymes that digest food, to sending messages to the brain about the book you are reading.

A signal transduction pathway involves a signal, a receptor, transduction, and effects

The entire signaling process, from signal detection to final response, is called a signal transduction pathway. Let's look at an example of such a pathway in E. coli (Figure 15.2). In Chapter 13, we saw that this bacterium responds to changes in the nutrient content of its environment by altering its transcription of certain genes, such as those in the lac operon. The bacterium must also be able to sense and respond to other kinds of changes in its environment, such as changes in solute concentration.

In the human intestine, where E. coli lives, the solute concentration around the bacterium often rises far above that inside the cell. The principle of diffusion tells us that when this happens, water will diffuse out of the cell and solutes will move into the cell. But the bacterium must maintain

Solutes enter the space between the two membranes through large pores in the outer membrane of E. coli.

15.2 A Model Signal Transduction Pathway E. coli responds to an increase in solute concentration in its environment.The basic steps of this pathway occur in all living organisms.

Solutes enter the space between the two membranes through large pores in the outer membrane of E. coli.

Solute (signal)

su uwjmu mm/I

Solute (signal)

Plasma membrane

The EnvZ membrane protein changes shape in response to the high solute concentration, catalyzing the addition of a phosphate from ATP.

The phosphate from EnvZ is transferred to the OmpR protein

.. .and the phosphorylated OmpR changes shape, enabling it to bind to DNA and stimulate transcription of the ompC gene.

OmpC protein inserts into the outer membrane, preventing solute entry and keeping the cell's exterior osmotically balanced.

Plasma Membrane

Cell wall

Intermembrane space

Outer membrane of bacterium /

Environment

Receptor

Plasma membrane

The EnvZ membrane protein changes shape in response to the high solute concentration, catalyzing the addition of a phosphate from ATP.

Transduction

The phosphate from EnvZ is transferred to the OmpR protein

.. .and the phosphorylated OmpR changes shape, enabling it to bind to DNA and stimulate transcription of the ompC gene.

OmpC protein inserts into the outer membrane, preventing solute entry and keeping the cell's exterior osmotically balanced.

Cell wall homeostasis, so it must perceive and respond to this environmental change. The pathway by which E. coli does so has much in common with signal transduction pathways in more complex animals and plants. The pathway involves two major components: a receptor and a responder.

receptor. A receptor is the first component of a signal transduction pathway. The receptor protein in E. coli for changes in solute concentration is called EnvZ. It is a transmembrane protein that extends through the bacterium's plasma membrane into the space between the plasma membrane and the highly porous outer membrane, which forms a complex with the cell wall. When the solute concentration of the extracellular environment rises, so does the solute concentration in the space between the two membranes. This change in its aqueous medium causes the part of the receptor protein sticking into the intermembrane space to undergo a conformational change.

As we saw in Chapter 6, changing the tertiary structure of one part of a protein often leads to changes in distant parts of the protein. In the case of the bacterial EnvZ receptor, the con-formational change in the intermembrane domain of the protein is transmitted to the domain that lies in the cytoplasm, initiating the events of signal transduction. Through this con-formational change, EnvZ becomes an active protein kinase, which catalyzes the addition of a phosphate group from ATP to one of EnvZ's own histidine residues. In other words, EnvZ phosphorylates itself.

o responder. A responder is the sec o ° ond component of a signal transduc-

„ o tion pathway. The charged phos phate group added to the histidine causes the cytoplasmic domain of the EnvZ protein to change its shape again. It now binds to a second protein, OmpR, which takes the phosphate group from EnvZ. This phosphorylation changes the shape of OmpR in turn. This change in a responder is a key event in signaling for three reasons:

► The signal on the outside of the cell has now been transduced to a protein totally within the cell's cytoplasm.

► The phosphorylated OmpR can do something. That "something" is to bind to a promoter on E. coli DNA adjacent to the sequence that codes for the protein OmpC. This binding begins the final phase of the signal-

Signal

Effects ing pathway: the effect of the signal, which is an alteration in cell function.

► The signal has been amplified. Because a single enzyme can catalyze the conversion of many substrate molecules, one EnvZ molecule alters the structure of many OmpR molecules.

Phosphorylated OmpR is a transcription factor with the correct three-dimensional structure to bind to the promoter of the ompC gene, resulting in an increase in the transcription of that gene. Translation of ompC mRNA results in the production of OmpC protein, which leads to the response that regulates osmotic pressure. The OmpC protein is inserted into the outer membrane of the bacterial cell, where it blocks pores and prevents solutes from entering the intermembrane space. As a result, the solute concentration in the intermembrane space is lowered, and osmotic balance is restored. Thus the E. coli cell can go on behaving just as if the external environment had a normal osmotic concentration.

Let's highlight the major features of this prokaryotic system, as the same elements will reappear in many other signal transduction pathways in animals and plants:

► A receptor changes its conformation upon binding with a signal.

► A conformational change in the receptor results in protein kinase activity.

► Phosphorylation alters the function of a responder protein.

► The signal is amplified.

► A transcription factor is activated.

► The synthesis of a specific protein is turned on.

► The action of the protein alters cell activity.

Now that we have surveyed the general features of signal transduction pathways, let's consider more closely the nature of the receptors that bind signals.

Receptors

Although a given cell in a multicellular organism is bombarded with many signals, it responds to only a few of them. The reason for this is that any particular cell makes receptors for only some signals. Which cells make which receptors is determined by the regulatory processes we studied in the previous chapter: If a cell transcribes the gene encoding a particular receptor and the resulting mRNA is translated, the cell will have that receptor.

A receptor protein binds to a signal very specifically, in much the same way as an enzyme binds to a substrate or a carrier protein binds to the molecule it is transporting across a membrane. This specificity of binding underlies the specificity of which cells respond to which signals.

Receptors have specific binding sites for their signals

A specific signal molecule fits into a site on its receptor much as a substrate fits into the active site of an enzyme (Figure 15.3). A molecule that binds to a receptor site in another molecule in this way is called a ligand. Binding of the ligand causes the receptor protein to change its three-dimensional structure, and that conformational change initiates a cellular response. The ligand does not contribute further to this response. In fact, the ligand usually is not metabolized into useful products. Its role is purely to "knock on the door." This is in sharp contrast to enzyme-substrate interactions, in which the whole purpose is to change the substrate into a useful product.

Receptors bind to their ligands according to chemistry's law of mass action:

This means that the binding is reversible, although for most ligand-receptor complexes, the equilibrium point is far to the right—that is, they favor binding. Reversibility is important, however, because if the ligand were never released, the receptor would be continuously stimulated.

The binding of a ligand to a receptor is similar in many ways to the binding of a substrate to an enzyme. As with enzymes, inhibitors can bind to the ligand binding site on a receptor protein. Both natural and artificial inhibitors of receptor binding are important in medicine. For example, many of the drugs that alter human behavior bind to specific receptors in the brain. Just as there are many types of enzymes with diverse specificities, there are many kinds of receptors.

Membrane Bound Receptor Image
15.3 A Signal Bound to Its Receptor Human growth hormone is shown bound to its receptor, a transmembrane protein. Only the extracellular regions of the receptor are shown.

There are several types of receptors

A major division among receptors is in their cellular location, which largely depends on the nature of their ligands. The chemistry of signal molecules is quite variable, but they can be divided into two classes (Figure 15.4):

► Ligands with cytoplasmic receptors: Small and/or nonpolar ligands can diffuse across the lipid 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 and enter the cell; it binds to a receptor in the cytoplasm.

► Ligands with plasma membrane receptors: Large and/or polar ligands cannot cross the plasma membrane. Insulin, for example, is a protein hormone that cannot diffuse through the plasma membrane; instead, it binds to a receptor that is a transmembrane protein with an extracellular binding domain.

In complex eukaryotes such as mammals, there are three well-studied types of receptors on plasma membranes: ion channels, protein kinases, and G protein-linked receptors.

ion channel receptors. In the plasma membranes of many types of cells are channel proteins that can be open or closed. These ion channels act as "gates," allowing ions such as Na+, K+, Ca2+, or Cl- to enter or leave the cell. The gate-opening mechanism is an alteration in the three-dimensional structure of the channel protein upon ligand binding. Some ion channels are membrane receptors for signal molecules; others act later in signal transduction pathways. Each type of ion channel receptor has its own signal. These signals include sensory stimuli, such as light and sound, charge differences across the plasma membrane, and chemical ligands such as hormones and neuro-transmitters.

The acetylcholine receptor, which is located at the plasma membranes of vertebrate skeletal muscle cells, is an example of a gated ion channel. This receptor protein binds the ligand acetylcholine, which is released from nerve cells (Figure 15.5). When two molecules of acetylcholine bind to the receptor, it opens for about a thousandth of a second. That is enough time for Na+, which is more concentrated outside the cell than inside, to rush into the cell. The change in Na+ concentration in the cell results in muscle contraction.

protein kinases. Like the EnvZ protein of E. coli, some eukaryotic receptor proteins become protein kinases when they are activated: that is, they catalyze the transfer of a phosphate group from ATP to a specific protein, referred to as the target protein. This phosphorylation can alter the conformation and activity of the target protein.

The receptor for insulin is an example of a protein kinase receptor. Insulin is a protein hormone made by the mammalian pancreas. Its receptor has two copies each of two different polypeptide subunits (Figure 15.6). As with acetyl-choline, two molecules of insulin must bind to the receptor. When insulin binds to its extracellular subunits, the recep-

Outside of cell

Nonpolar signal

Transmembrane receptor

Polar signal

Outside of cell

Nonpolar signal

Transmembrane receptor

Polar signal

A nonpolar signal can diffuse directly across the lipid bilayer of the plasma membrane to encounter its receptor in the cytoplasm.

A signal that is polar and/or large cannot diffuse through the plasma membrane. Its receptor is embedded in the membrane.

A nonpolar signal can diffuse directly across the lipid bilayer of the plasma membrane to encounter its receptor in the cytoplasm.

A signal that is polar and/or large cannot diffuse through the plasma membrane. Its receptor is embedded in the membrane.

Outside of cell O

|11 Acetylcholine binds to two of the five AChR subunits, causing the channel to change shape and open.

Outside of cell O

|11 Acetylcholine binds to two of the five AChR subunits, causing the channel to change shape and open.

Acetylcholine (ACh)

The channel is lined with negatively charged amino acids, allowing Na+ to flow into the cell.

Na+ buildup in cells leads to muscle contraction.

Acetylcholine receptor (AChR)

Inside of cell

15.5 A Gated Ion Channel The acetylcholine receptor (AChR) is a gated ion channel for sodium ions.It is made up of five polypeptide subunits.When acetylcholine molecules (ACh) bind to two of the subunits, the gate opens and Na+ flows into the cell.

Acetylcholine receptor (AChR)

Inside of cell

Acetylcholine (ACh)

The channel is lined with negatively charged amino acids, allowing Na+ to flow into the cell.

Na+ buildup in cells leads to muscle contraction.

Inside of cell

15.4 Two Locations for Receptors Receptors can be located in the plasma membrane or in the interior of the cell.

15.5 A Gated Ion Channel The acetylcholine receptor (AChR) is a gated ion channel for sodium ions.It is made up of five polypeptide subunits.When acetylcholine molecules (ACh) bind to two of the subunits, the gate opens and Na+ flows into the cell.

"I

The a subunit binds insulin (the signal).

Insulin

| A conformational change in the P subunits transmits a signal to the cytoplasm that insulin is present.

The a subunit binds insulin (the signal).

Insulin

| A conformational change in the P subunits transmits a signal to the cytoplasm that insulin is present.

The insulin signal activates the receptor's protein kinase domain in the cytoplasm...

Insulin receptor

Insulin' response substrate (IRS)

Cellular responses

15.6 A Protein Kinase Receptor The mammalian hormone insulin does not enter the cell, but is bound by the extracellular domain of a receptor protein with four subunits (two a and two P). Binding to the a subunit causes a conformational change in the cytoplasmic domain of the P subunits, exposing a protein kinase active site.This protein kinase activity phosphorylates insulin response substrate proteins, triggering further responses within the cell and eventually resulting in the transport of glucose across the membrane into the cell.

The insulin signal activates the receptor's protein kinase domain in the cytoplasm...

Insulin receptor

Insulin' response substrate (IRS)

Inside of cell

Cellular responses which phosphorylates insulin-response substrates, triggering a cascade of chemical responses inside the cell.

tor changes its shape to expose a cytoplasmic protein kinase active site. Like the EnvZ receptor described above, the insulin receptor autophosphorylates. Then, as a protein kinase, it catalyzes the phosphorylation of certain cytoplasmic proteins, appropriately called insulin response substrates. These proteins then initiate many cellular responses, including the insertion of glucose transporters into the plasma membrane.

g protein-linked receptors. A third category of eukaryot-ic plasma membrane receptors is the seven-spanning G protein-linked receptors. This long name identifies a fascinating group of receptors, all of which are composed of a single protein with seven regions that pass through the lipid bilayer, separated by short loops that extend either outside or inside the cell. Ligand binding on the extracellular side of the receptor changes the shape of its cytoplasmic region, exposing a binding site for a mobile membrane protein.

This membrane protein, known as a G protein, has two important binding sites: one for the G protein-linked receptor and the other for the nucleotide GDP/GTP (Figure 15.7). G proteins have several polypeptide subunits. When the G protein binds to the activated receptor, one of its subunits binds GTP. At the same time, the ligand is released from the extracellular side of the receptor. The GTP-bound subunit of the G protein now separates from the parent G protein, diffusing in the plane of the lipid bilayer until it encounters an effector protein to which it can bind.

An effector protein is just what its name implies: It causes an effect in the cell. The binding of the GTP-bearing G protein subunit activates the effector—which may be an enzyme or an ion channel—thereby causing changes in cell function.

After binding to the effector protein, the GTP on the G protein is hydrolyzed to GDP. The now inactive G protein

15.7 A G Protein-Linked Receptor Binding of an extracellular signal—in this case, a hormone—causes the activation of a G protein-linked receptor.The G protein then activates an effector protein—in this case, an enzyme that catalyzes a reaction in the cytoplasm, amplifying the signal. This figure is a generalized diagram that could apply to any member of the large family of G proteins and the signals they react to.

The actions of several membrane-associated proteins are required to convert the signal from a hormone to an amplified response in the cell.

| Hormone binding provides a signal that activates the G protein.

2l 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.

The actions of several membrane-associated proteins are required to convert the signal from a hormone to an amplified response in the cell.

| Hormone binding provides a signal that activates the G protein.

2l 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.

Amplification

1 c

(j—igDP \

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Essentials of Human Physiology

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