5

CHAPTER

Cell Signaling in Physiology

5.1 Receptors
5.2 Signal Transduction Pathways
Chapter 5 Clinical Case Study

Computerized image of a ligand (ball and stick model in blue) binding

to its receptor (ribbon diagram). Dr. Mark J. Winter/Science Source

Y
ou learned in Chapter 1 how homeostatic control systems help
maintain a normal balance of the body’s internal environment.
The operation of control systems requires that cells be able to
communicate with each other, often over long distances. Much of this
intercellular communication is mediated by chemical messengers.
This chapter describes how these messengers interact with their target
cells and how these interactions trigger intracellular signals that lead
to the cell’s response. Throughout this chapter, you should carefully
distinguish intercellular (between cells) and intracellular (within a
cell) chemical messengers and communication. The material in this
chapter will provide a foundation for understanding how the nervous,
endocrine, and other organ systems function. Before starting, you
should review the material covered in Chapter 3 for background on
ligand–protein interactions.
The material in this chapter illustrates the general principle of
physiology that information flow between cells, tissues, and organs
is an essential feature of homeostasis and allows for integration
of physiological processes. These many and varied processes will
be covered in detail beginning in Chapter 6 and will continue
throughout the book, but the mechanisms of information flow that
link different structures and processes share many common features,
as described here. ■

118
5.1 Receptors This is one key distinction between the two general types of recep-
tors; plasma membrane receptors can transduce signals without
In Chapter 1, you learned that several classes of chemical mes- interacting with DNA, whereas all intracellular receptors trans-
sengers can communicate a signal from one cell to another. These duce signals through interactions with genes.
messengers include molecules released from neurons or nearby
cells, which can reach and act on the target cell rapidly due to the Interactions Between Receptors and Ligands
short distances the signal must travel. Other messengers, such as There are four major features that define the interactions between
hormones, communicate over greater distances and, in some cases, receptors and their ligands: specificity, affinity, saturation, and
more slowly. Whatever the chemical messenger, however, the cell competition.
receiving the signal must have a way to detect the signal’s presence.
Once a cell detects a signal, a mechanism is required to transduce Specificity
that signal into a physiologically meaningful response, such as the The binding of a chemical messenger to its receptor initiates
cell-division response to the delivery of growth-promoting signals. the events leading to the cell’s response. The existence of recep-
The first step in the action of any intercellular chemical tors explains a very important characteristic of intercellular
messenger is the binding of the messenger to specific target- communication—specificity (see Table 5.1 for a glossary of
cell proteins known as receptors (or receptor proteins). In the terms concerning receptors). As described in Chapter 3 (refer back
general language of Chapter 3, a chemical messenger is a ligand, to Figures 3.28 and 3.29), a given protein binds a particular ligand
and the receptor has a binding site for that ligand. The binding and not others if its binding site for that ligand is specific. This
of a messenger to a receptor changes the conformation (tertiary is generally the case for chemical messengers and their recep-
structure; see Figure 2.17) of the receptor, which activates it. tors. Thus, although a given chemical messenger may come into
This initiates a sequence of events in the cell leading to the cell’s contact with many different cells, it influences certain cell types
response to that messenger, a process called signal transduction. and not others. This is because cells differ in the types of recep-
The “signal” is the receptor activation, and “transduction” denotes tors they possess. Only certain cell types—sometimes just one—
the process by which a stimulus is transformed into a response. In express the specific receptor required to bind a given chemical
this section, we consider general features common to many recep- messenger (Figure 5.2).
tors, describe interactions between receptors and their ligands, In the case where many different cell types possess receptors
and give some examples of how receptors are regulated. for the same messenger, however, the responses of the various cell
types to that messenger may differ from each other. For example,
Types of Receptors the neurotransmitter norepinephrine causes muscle cells of the
What is the nature of the receptors that bind intercellular chemical heart to contract faster but, via the same type of receptor, regulates
messengers? They are proteins or glycoproteins located either in certain aspects of behavior by acting on neurons in the brain. In
the cell’s plasma membrane or inside the cell, either in the cytosol essence, then, the receptor functions as a molecular switch that elic-
or the nucleus. The plasma membrane is the much more common its the cell’s response when “switched on” by the messenger binding
location, because a very large number of messengers are water- to it. Just as identical types of switches can be used to turn on a light
soluble and therefore cannot diffuse across the lipid-rich (hydro- or a radio, a single type of receptor can be used to produce different
phobic) plasma membrane. In contrast, a much smaller number responses to the same chemical m ­ essenger in different cell types.
of lipid-soluble messengers diffuse through membranes to bind to
their receptors located inside the cell. Affinity
The remaining three general features of ligand-receptor interac-
Plasma Membrane Receptors tions are summarized in Figure 5.3. The degree to which a partic-
A typical plasma membrane receptor is illustrated in Figure 5.1a. ular messenger binds to its receptor is determined by the affinity
Plasma membrane receptors are transmembrane proteins­—that is, of the receptor for the messenger. A receptor with high affinity
they span the entire membrane thickness. Like other transmembrane will bind at lower concentrations of a messenger than will a recep-
proteins, a plasma membrane receptor has hydrophobic segments tor of low affinity (refer back to Figure 3.36). Differences in affin-
within the membrane, one or more hydrophilic segments extend- ity of receptors for their ligands have important implications for
ing out from the membrane into the extracellular fluid, and other the use of therapeutic drugs in treating illness; receptors with high
hydrophilic segments extending into the intracellular fluid. Arriving affinity for a ligand require much less of the ligand (that is, a lower
chemical messengers bind to the extracellular parts of the receptor; dose) to become activated.
the intracellular regions of the receptor are involved in signal trans-
duction events. Saturation
The phenomenon of receptor saturation was described in Chapter 3
Intracellular Receptors for ligands binding to binding sites on proteins, and it is fully
By contrast, intracellular receptors are not located in membranes applicable here (see Figure 5.3). A cell’s response to a messen-
but exist in either the cytosol or the cell nucleus and have a very ger increases as the extracellular concentration of the messenger
different structure (Figure 5.1b). Like plasma membrane recep- increases, because the number of receptors occupied by messenger
tors, however, they have a segment that binds the messenger and molecules increases. There is an upper limit to this responsiveness,
other segments that act as regulatory sites. In addition, they have however, because only a finite number of receptors are available,
a segment that binds to DNA, unlike plasma membrane receptors. and at some point they become fully saturated.

Cell Signaling in Physiology 119

 CHO
CHO
NH2

Extracellular fluid
Hormone-
binding site

Plasma
membrane

HOOC
Intracellular fluid

(a) Transmembrane receptor for a hormone

Estrogen Estrogen receptor Differences in the

receptor DBD LBD shapes of the ligand-
binding domains
DNA determine which
messenger binds to
Subtle differences in the structure a given receptor.
of this domain determine which
segments of DNA are bound by
different receptors. Estrogen

DNA-binding Hinge Ligand-binding

NH2 – N-terminal domain domain (DBD) domain
– COOH
domain (LBD)

This domain This domain

participates in is required
gene activation. for nuclear
receptors
to localize in
a cell nucleus.
(b) Nuclear receptor showing domain structure

Figure 5.1 The two major classes of receptors for chemical messengers. (a) Structure of a typical transmembrane receptor. The seven clusters of
amino acids embedded in the phospholipid bilayer represent hydrophobic portions of the protein’s alpha helix (shown here as cylinders). Note that the
binding site for the hormone includes several of the segments that extend into the extracellular fluid. Portions of the extracellular segments can be
linked to carbohydrates (CHO). The amino acids denoted by black circles represent some of the sites at which intracellular enzymes can phosphorylate,
and thereby regulate, the receptor. (b) Schematic representation of the structural features of a typical nuclear receptor. The actual structures for
segments of these receptors are known and are shown here for the human estrogen (a steroid hormone) receptor. (Note: The segments of proteins—
including those of nuclear receptors—that perform different functions are known as “domains.”)

120 Chapter 5
 A Glossary of Terms Concerning
TABLE 5.1 Receptors Secretory cell

Receptor A specific protein in either the plasma membrane

(receptor or the interior of a target cell that a chemical
protein) messenger binds with, thereby invoking a Chemical messenger
biologically relevant response in that cell.

Specificity The ability of a receptor to bind only one type

or a limited number of structurally related Receptor
types of chemical messengers. Only cells
that express the correct receptor can bind a
particular messenger. Cell A Cell B Cell C

Saturation The degree to which receptors are occupied by

messengers. If all are occupied, the receptors
Response
are fully saturated; if half are occupied, the
saturation is 50%, and so on.
Figure 5.2 Specificity of receptors for chemical messengers.
Only cell A has the appropriate receptor for this chemical messenger;
Affinity The strength with which a chemical messenger
therefore, it is the only one among the group that is a target cell for the
binds to its receptor.
messenger.
Competition The ability of different molecules to compete
with a ligand for binding to its receptor. Chemical High-affinity receptor
Competitors generally are similar in structure messenger

Amount of messenger bound

Receptor
to the natural ligand.
Competitor
Antagonist A molecule that competes with a ligand for
binding to its receptor but does not activate
signaling normally associated with the natural High-affinity receptor in
ligand. Therefore, an antagonist prevents the presence of competitor
actions of the natural ligand. Certain types of
antihistamines are examples of antagonists. Low-affinity receptor

Agonist A chemical messenger that binds to a receptor

and triggers the cell’s response; often refers to a Free messenger concentration X
drug that mimics a normal messenger’s action.
Some decongestants are examples of agonists. Figure 5.3 Characteristics of receptors binding to messengers. The
receptors with high affinity will have more bound messenger at a given
Down- A decrease in the total number of target-cell messenger concentration (e.g., concentration X). The presence of a
regulation receptors for a given messenger; may occur competitor will decrease the amount of messenger bound, until at very
in response to chronically high extracellular high concentrations the receptors become saturated with messenger
concentration of the messenger. and cannot bind any additional messenger. Note in the illustration that
the low-affinity receptor in this case has a slightly different shape in
Up-regulation An increase in the total number of target-cell its ligand-binding region compared to the high-affinity receptor, which
receptors for a given messenger; may occur makes it less able to bind the messenger. Also note the similarity in
in response to a chronically low extracellular parts of the shapes of the natural messenger and its competitor.
concentration of the messenger.
DIG DEEPER: General Principle of Physiology
Increased The increased responsiveness of a target
sensitivity cell to a given messenger; may result from ■ The general principle of physiology that structure is a determinant
up-regulation of receptors. of—and has coevolved with—function can be considered at
the molecular, cellular, and organ levels. How is this principle
illustrated by the binding of messengers to their receptors?
Answer found in Appendix A.
Competition
Competition refers to the ability of a molecule to compete with
a natural ligand for binding to its receptor. Competition typi- the endogenous messenger that they bind to the receptors for
cally occurs with messengers that have a similarity in part of that messenger. However, the competing molecules are differ-
their structures, and it also underlies the action of many drugs ent enough in structure from the native ligand that, although
(see Figure 5.3). If researchers or physicians wish to interfere they bind to the receptor, they cannot activate it. This blocks
with the action of a particular messenger, they can administer the endogenous messenger from binding and yet does not induce
competing molecules that are structurally similar enough to signal transduction or trigger the cell’s response.
Cell Signaling in Physiology 121
 The general term for a compound that blocks the action of the likelihood that such binding will occur. For example, when the
a chemical messenger is antagonist; when an antagonist works nerves to a muscle are damaged, the delivery of neurotransmitters
by competing with a chemical messenger for its binding site, it is from those nerves to the muscle is decreased or eliminated. With
known as a competitive antagonist. One example is a type of drug time, under these conditions, the muscle will contract in response
called a beta-adrenergic receptor blocker (also called beta-blocker), to a much smaller amount of neurotransmitter than normal. This
which is sometimes used in the treatment of high blood pres- happens because the receptors for the neurotransmitter have been
sure and other diseases. Beta-blockers compete with epinephrine up-regulated, resulting in increased sensitivity.
and norepinephrine to bind to one of their receptors—the beta- One way in which up-regulation may occur is by recruitment
adrenergic receptor. Because one of the normal functions of to the plasma membrane of intracellular vesicles that contain within
epinephrine and norepinephrine is to increase blood pressure their membranes numerous receptor proteins. The vesicles fuse
(Chapter 12), beta-blockers tend to decrease blood pressure by act- with the plasma membrane, thereby inserting their receptors into the
ing as competitive antagonists. Antihistamines are another exam- plasma membrane. Receptor regulation in both directions (up- and
ple of an antagonist and are useful in treating allergic symptoms down-regulation) is an excellent example of the general physiologi-
brought on due to excess histamine secretion from cells known as cal principle of homeostasis, because such regulation acts to return
mast cells (Chapter 18). Certain antihistamines are competitive signal strength toward normal when the concentration of messenger
antagonists that block histamine from binding to its receptors on molecules varies above or below normal.
mast cells and triggering an allergic response.
On the other hand, some drugs that compete with natural
ligands for a particular receptor type do activate the receptor
and trigger the cell’s response exactly as if the true (endogenous) St udy and Review 5.1
chemical messenger had combined with the receptor. Such drugs,
■ Receptors for chemical messengers are proteins or
known as agonists, are used therapeutically to mimic the mes-
glycoproteins located inside the cell or in the plasma
senger’s action. For example, the common decongestant drugs
membrane.
phenylephrine and oxymetazoline, found in many types of nasal
sprays, mimic the action of epinephrine on a related but differ- ■ Signal transduction: a sequence of events inside a cell
ent subtype of receptors, called alpha-adrenergic receptors, in beginning with a receptor binding a chemical messenger and
blood vessels. When alpha-adrenergic receptors are activated, ending with a cell’s response to that messenger
the smooth muscles of inflamed, dilated blood vessels in the nose ■ Binding of a messenger by a receptor demonstrates specificity,
contract, resulting in narrowing of those vessels; this helps open saturation, and competition.
the nasal passages and decrease fluid leakage from blood vessels. ∙∙ Agonists: drugs that mimic a messenger’s actions by binding
to and activating the messenger’s receptor
∙∙ Antagonists: drugs that inhibit a messenger’s actions by
Regulation of Receptors binding to and inhibiting the messenger’s receptor
Receptors are themselves subject to physiological regulation.
■ Receptors are subject to physiological regulation by their own
The number of receptors a cell has, or the affinity of the recep-
messengers.
tors for their specific messenger, can be increased or decreased
in certain systems. An important example is the phenomenon of ∙∙ Up-regulation: the numbers of receptors are increased by
their messenger; may result in increased sensitivity to the
down-regulation. When a high extracellular concentration of a
messenger
messenger is maintained for some time, the total number of the
∙∙ Down-regulation: the numbers of receptors are decreased
target cell’s receptors for that messenger may decrease—that is,
by their messenger via the process of internalization;
down-regulate. Down-regulation has the effect of reducing the
compensates for chronically elevated extracellular
target cells’ responsiveness to frequent or intense stimulation by concentrations of a messenger
a messenger—that is, desensitizing them—and thus represents a
local negative feedback mechanism. ■ Different cell types express different types of receptors.
Down-regulation is possible because there is a continuous ∙∙ A single cell may express multiple receptor types.
synthesis and degradation of receptors. The main mechanism of Review Question: What are some advantages to cells expressing
down-regulation of plasma membrane receptors is internalization. receptors for particular extracellular messengers? (Answer found
The binding of a messenger to its receptor can stimulate the inter- in Appendix A.)
nalization of the complex—that is, the messenger-receptor com-
plex is taken into the cell by receptor-mediated endocytosis (see
Chapter 4). This increases the rate of receptor degradation inside
the cell. Consequently, at increased messenger concentrations, 5.2 Signal Transduction
the number of plasma membrane receptors of that type gradually
decreases during down-regulation.
Pathways
Change in the opposite direction, called up-regulation, also What are the sequences of events by which the binding of a chemical
occurs. Cells exposed for a prolonged period to very low concentra- messenger to a receptor causes the cell to respond in a specific way?
tions of a messenger may come to have many more receptors for The binding of a messenger to its receptor causes a change
that messenger, thereby developing increased sensitivity to it. The in the conformation (tertiary structure) of the receptor. This event,
greater the number of receptors available to bind a ligand, the greater known as receptor activation, is the initial step leading to the
122 Chapter 5
cell’s responses to the messenger. These cellular responses can Capillary
take the form of changes in:
M Lipid-soluble
■■ the permeability, transport properties, or electrical state of messenger
the plasma membrane Target cell Interstitial fluid
■■ metabolism Plasma
membrane
■■ secretory activity M Messenger-receptor
■■ rate of proliferation and differentiation complex
■■ contractile or other activities Nucleus
M
Despite the variety of responses, there is a common denom-
inator: They are all directly due to alterations of particular cell Cellular
M
proteins. Let us examine a few examples of messenger-induced response
responses, all of which are described more fully in subsequent
chapters. For example, the neurotransmitter-induced generation of Specific M
receptor
electrical signals in neurons reflects the altered conformation of Protein
membrane proteins (ion channels) through which ions can diffuse synthesis
DNA
between extracellular and intracellular fluid. Similarly, changes
in the rate of glucose secretion by the liver induced by the hor-
mRNA
mone epinephrine reflect the altered activity and concentration of
enzymes in the metabolic pathways for glucose synthesis. Finally,
muscle contraction induced by the neurotransmitter acetylcholine
results from the altered conformation of contractile proteins.
Thus, receptor activation by a messenger is only the first
step leading to the cell’s ultimate response (contraction, secre-
tion, and so on). The diverse sequences of events that link receptor
activation to cellular responses are termed signal transduction
pathways. “Pathways” denotes the cell-specific mechanisms Figure 5.4 Mechanism of action of lipid-soluble messengers.
linked with different messengers. This figure shows the receptor (simplified in this view) for these
Signal transduction pathways differ between lipid-soluble messengers in the nucleus. In some cases, the unbound receptor is
and water-soluble messengers. As described, the receptors for in the cytosol rather than the nucleus, in which case the binding occurs
these two broad chemical classes of messenger are in different there, and the activated messenger-receptor complex then moves
locations—the former inside the cell and the latter in the plasma into the nucleus. For simplicity, a single messenger is shown binding
membrane of the cell. The rest of this chapter describes the major to a single receptor. In many cases, however, two messenger-receptor
complexes must bind together in order to activate a gene.
features of the signal transduction pathways that these two broad
categories of messengers initiate.
DIG DEEPER: General Principle of Physiology
Pathways Initiated by Lipid-Soluble ■ How does the chemical nature of lipid-soluble messengers relate
Messengers to the general principle of physiology that physiological processes
are dictated by the laws of chemistry and physics?
Lipid-soluble messengers include hydrophobic substances such as
steroid hormones and thyroid hormone. Their receptors belong to Answer found in Appendix A.
a large family of intracellular receptors called nuclear receptors
that share similar structures (see Figure 5.1b) and mechanisms
of action. Although plasma membrane receptors for a few of transcription. The hormone–receptor complex binds to DNA at a
these messengers have been identified, most of the receptors in regulatory region of a gene, an event that typically increases the
this family are intracellular. In a few cases, the inactive receptors rate of that gene’s transcription into mRNA. The mRNA molecules
are located in the cytosol and move into the nucleus after bind- move out of the nucleus to direct the synthesis, on ribosomes, of the
ing their ligand. In most cases, however, the inactive receptors protein the gene encodes. The result is an increase in the cellular
already reside in the cell nucleus, where they bind to and are acti- concentration of the protein and/or its rate of secretion, accounting
vated by their respective ligands. In both cases, receptor activa- for the cell’s ultimate response to the messenger. For example, if
tion leads to altered rates of transcription of one or more genes in the protein encoded by the gene is an enzyme, the cell’s response
a particular cell. is an increase in the rate of the reaction catalyzed by that enzyme.
In the most common scenario, the messenger diffuses out Two other points are important. First, more than one gene
of capillaries from plasma to the interstitial fluid (refer back to may be subject to control by a single receptor type. For example,
Figure 1.3). From there, the messenger diffuses across the lipid the adrenal gland hormone cortisol acts via its intracellular recep-
bilayers of the plasma membrane and nuclear envelope to enter the tor to activate numerous genes involved in the coordinated control
nucleus and bind to its receptor there (Figure 5.4). The activated of cellular metabolism and energy balance. Second, in some cases,
receptor complex then functions in the nucleus as a transcription the transcription of a gene or genes may be decreased rather than
factor, defined as a regulatory protein that directly influences gene increased by the activated receptor. Cortisol, for example, inhibits
Cell Signaling in Physiology 123
transcription of several genes whose protein products mediate has been compared to the opening of a gate in a fence, these types
inflammatory responses that occur following injury or infection; of channels are known as ligand-gated ion channels, as described
for this reason, cortisol has important anti-inflammatory effects. in Chapter 4. They are particularly prevalent in the plasma
membranes of neurons and skeletal muscle, as you will learn in
Pathways Initiated by Water-Soluble Chapters 6 and 9.
Messengers The opening of ligand-gated ion channels in response to
binding of a first messenger results in an increase in the net dif-
Water-soluble messengers cannot readily enter cells by diffu-
fusion across the plasma membrane of one or more types of ions
sion through the lipid bilayer of the plasma membrane. Instead,
specific to that channel. As introduced in Chapter 4 (see Figure 4.6),
they exert their actions on cells by binding to the extracellular
such a change in ion diffusion results in a change in the electrical
portion of receptor proteins embedded in the plasma membrane.
charge, or membrane potential, of a cell. This change in mem-
Water-soluble messengers include most polypeptide hormones,
brane potential, then, is the cell’s response to the messenger. In
neurotransmitters, and paracrine and autocrine compounds. The
addition, when the channel is a Ca2+ channel, its opening results in
signal transduction mechanisms initiated by water-soluble messen-
an increase by diffusion in cytosolic Ca2+ concentration. Increas-
gers can be classified into the types illustrated in Figure 5.5.
ing cytosolic Ca2+ is another essential event in the transduction
Some notes on general terminology are essential for this
pathway for many signaling systems.
discussion. First, the extracellular chemical messengers (such as
hormones or neurotransmitters) that reach the cell and bind to their Signaling by Receptors That Function as Enzymes
specific plasma membrane receptors are often referred to as first Other plasma membrane receptors for water-soluble messengers
messengers. Second messengers, then, are substances that enter have intrinsic enzyme activity. With one major exception (dis-
or are generated in the cytoplasm as a result of receptor activation cussed later), the many receptors that possess intrinsic enzyme
by the first messenger. The second messengers diffuse throughout activity are all protein kinases (Figure 5.5b). Of these, the great
the cell to serve as chemical relays from the plasma membrane to majority specifically phosphorylate tyrosine residues. Conse-
the biochemical machinery inside the cell. quently, these receptors are known as receptor tyrosine kinases.
A third essential general term is protein kinase, which is the The typical sequence of events for receptors with intrinsic
name for an enzyme that phosphorylates other proteins by transfer- tyrosine kinase activity is as follows. The binding of a specific
ring a phosphate group to them from ATP. Phosphorylation of a pro- messenger to the receptor changes the conformation of the recep-
tein allosterically changes its tertiary structure and, consequently, tor so that its enzymatic portion, located on the cytoplasmic side
alters the protein’s activity. Different proteins respond differently of the plasma membrane, is activated. This results in autophos-
to phosphorylation; some are activated and some are inactivated phorylation of the receptor—that is, the receptor phosphorylates
(inhibited). There are many different protein kinases, and each type some of its own tyrosine residues. The newly created phospho-
is able to phosphorylate only specific proteins. The important point tyrosines on the cytoplasmic portion of the receptor then serve
is that a variety of protein kinases are involved in signal transduction as docking sites for cytoplasmic proteins. The bound docking
pathways. These pathways may involve a series of reactions in which proteins then bind and activate other proteins, which in turn acti-
a particular inactive protein kinase is activated by phosphorylation vate one or more signaling pathways within the cell. The common
and then catalyzes the phosphorylation of another inactive protein denominator of these pathways is that they all involve activation of
kinase, and so on. At the ends of these sequences, the ultimate phos- cytoplasmic proteins by phosphorylation.
phorylation of key proteins, such as transporters, metabolic enzymes, There is one physiologically important exception to the gen-
ion channels, and contractile proteins, underlies the cell’s response eralization that plasma membrane receptors with inherent enzyme
to the first messenger. Although all cells contain many of the same activity function as protein kinases. In this exception, the receptor
protein kinases, different cells often express specific proteins that functions both as a receptor and as a guanylyl cyclase to catalyze
are not necessarily found in other cells. Thus, a given protein kinase the formation, in the cytoplasm, of a molecule known as cyclic
may have different substrates in different cell types. GMP (cGMP). In turn, cGMP functions as a second messenger to
As described in Chapter 3, other enzymes do the reverse of activate a protein kinase, called cGMP-dependent protein kinase.
protein kinases—that is, they dephosphorylate proteins. These This kinase phosphorylates specific proteins that then mediate the
enzymes, termed protein phosphatases, also participate in signal cell’s response to the original messenger. As described in Chapter 7,
transduction pathways; they can also serve to stop a signal once a receptors that function both as ligand-binding molecules and as
cell response has occurred. guanylyl cyclases are abundantly expressed in the retina of the eye,
where they are important for processing visual inputs.
Signaling by Receptors That Are Ligand-Gated This signal transduction pathway is used by only a small
Ion Channels number of messengers. Also, in certain cells, guanylyl cyclase
In one type of plasma membrane receptor for water-soluble mes- enzymes are present in the cytoplasm. In these cases, a first
sengers, the protein that acts as the receptor is also an ion channel ­messenger—the gas nitric oxide (NO)—diffuses into the cytosol
(refer back to Figure 4.7). Recall from Chapter 3 (see Figure 3.32) of the cell and combines with the guanylyl cyclase to trigger the
that normally when a ligand binds to a protein, a shape change formation of cGMP. Nitric oxide is a lipid-soluble gas produced
is induced in the protein. Activation of the receptor by a first from the amino acid arginine by the action of an enzyme called
messenger (the ligand) results in a conformational change of the nitric oxide synthase, which is present in numerous cell types,
receptor such that it forms an open channel through the plasma including the cells that line the interior of blood vessels. When
membrane (Figure 5.5a). Because the opening of ion channels released from such cells, NO acts locally in a paracrine fashion
124 Chapter 5
 First messenger First messenger
Extracellular fluid Extracellular fluid
Open ion channel First messenger
Open ion channel First messenger
Extracellular fluid Ionfluid
Extracellular Ion

Plasma Plasma Receptor PlasmaReceptor Plasma

Receptor Receptor
membrane membrane membrane membrane
(bound) (bound)
(unbound) (unbound)

Change in Change in
Closed ion channel Closed ion channel membrane potential membrane potential
and/or and/or
cytosolic [Ca2+] cytosolic [Ca2+]

(multiple steps) (multiple steps)

Intracellular fluid CELL’S RESPONSE

Intracellular fluid CELL’S Intracellular
RESPONSE fluid Intracellular fluid

rane receptor with ion(a)channel in closed

Membrane (left)with ion channel in closed (left)
receptor
en (right) conformationsand open (right) conformations

First messenger First messenger

First messenger First messenger

Receptor Receptor
Receptor Receptor

Tyrosine kinase Tyrosine kinase

ATP
PO4 PO4
(multiple steps) (multiple steps) Janus kinase Janus kinase
ADP ADP
Docking Docking
protein protein
Protein + ATP Protein 4 + +ADP
Protein-PO ATP Protein-PO4 + ADP
Docking Docking
protein protein (multiple steps)
CELL’S RESPONSE CELL’S RESPONSE (multiple steps)
CELL’S RESPONSE CELL’S RESPONSE
brane receptor with enzymatic activity
(b) Membrane receptor with enzymatic activity
(c) Membrane receptor that activates janus kinase
(c) Membrane receptor that activates janus kinase

Figure 5.5 Mechanisms of action of water-soluble

First messenger First messenger messengers (noted as “first messengers” in this and subsequent
figures). (a) Signal transduction mechanism in which the receptor
complex includes an ion channel. Note that the receptor exists in two
conformations in the unbound and bound states. It is the binding of
Effector Effector
GDP GTP proteinGDP GTP theprotein
first messenger to its receptor that triggers the conformational
Receptor Receptor change that leads to opening of the channel. Note: Conformational
(ion channel (ion channel
or enzyme) changes
or enzyme)also occur in panels b–d but only the bound state is shown
for simplicity. (b) Signal transduction mechanism in which the
G Protein Generates
G Protein receptor itselfGenerates
functions as an enzyme, usually a tyrosine kinase.
(c) Signal transduction mechanism in which the receptor activates
Change in Second Change ainjanus kinase in the cytoplasm. (d) Signal transduction mechanism
Second
membrane potential messengers involving G
membrane potential proteins. When GDP is bound to the alpha subunit of the
messengers
G protein, the protein exists as an inactive trimeric molecule. Binding
of GTP to the alpha subunit causes dissociation of the alpha subunit,
(multiple steps)
which then activates the effector protein.
(multiple steps)

CELL’S RESPONSE
DIG DEEPER
CELL’S RESPONSE
■ Many cells express more than one of the four types of
(d) Membrane receptor linked with G protein receptor linked with G protein
(d) Membrane
receptors depicted in this figure. Can you think of any
benefits that this might confer in terms of the regulation of
cell function?
Answer found in Appendix A.
to relax the smooth muscle component of certain blood vessels, may be associated with more than one type of G protein. More-
which allows the blood vessel to dilate, or open, more. As you will over, some G proteins may couple to more than one type of plasma
learn in Chapter 12, the ability of certain blood vessels to dilate membrane effector protein. In this way, a first-messenger-activated
is an important part of the homeostatic control of blood pressure. receptor, via its G-protein couplings, can call into action a variety
of plasma membrane proteins such as ion channels and enzymes.
Signaling by Receptors That Interact with Cytoplasmic These molecules can, in turn, induce a variety of cellular events.
Janus Kinases To illustrate some of the major points concerning G proteins,
Recall that in the previous category, the receptor itself has intrinsic plasma membrane effector proteins, second messengers, and protein
enzyme activity. In the next category of signal transduction mecha- kinases, the next two sections describe the two most common effec-
nisms for water-soluble messengers (Figure 5.5c), the enzymatic tor protein enzymes regulated by G proteins—adenylyl cyclase and
activity—again, tyrosine kinase activity—resides not in the receptor phospholipase C. In addition, the subsequent portions of the signal
but in a family of separate cytoplasmic kinases, called janus kinases transduction pathways in which they participate are described.
(JAKs), which are associated with the receptor. In these cases, the
receptor and its associated janus kinase function as a unit. The bind- Major Second Messengers
ing of a first messenger to the receptor causes a conformational
change in the receptor that leads to activation of the janus kinase. Cyclic AMP
Different receptors associate with different members of the In this pathway (Figure 5.6), activation of the receptor by the
janus kinase family, and the different janus kinases phosphorylate dif- binding of the first messenger (for example, the hormone epineph-
ferent target proteins, many of which act as transcription factors. The rine) allows the receptor to activate its associated G protein, in this
result of these pathways is the synthesis of new proteins, which medi- example known as Gs (the subscript s denotes “stimulatory”). This
ate the cell’s response to the first messenger. One significant example causes Gs to activate its effector protein, the plasma membrane
of signals mediated primarily via receptors linked to janus kinases enzyme called adenylyl cyclase (also known as adenylate cyclase).
are those of the cytokines—proteins secreted by cells of the immune The activated adenylyl cyclase, with its catalytic site located on
system that have a critical function in immune defenses (Chapter 18). the cytosolic surface of the plasma membrane, catalyzes the con-
version of cytosolic ATP to 3′,5′-cyclic adenosine monophosphate,
Signaling by G-Protein-Coupled Receptors or cyclic AMP (cAMP) (Figure 5.7).
The fourth category of signaling pathways for water-soluble mes- Once formed, cAMP acts as a second messenger (see Fig-
sengers is by far the largest, including hundreds of distinct recep- ure 5.6). It diffuses throughout the cell to trigger the sequence
tors (Figure 5.5d). Bound to the inactive receptor is a protein of events leading to the cell’s ultimate response to the first
complex located on the cytosolic surface of the plasma membrane messenger. The action of cAMP eventually terminates when it is
and belonging to the family of proteins known as G proteins. broken down to AMP, a reaction catalyzed by the enzyme cAMP
G proteins contain three subunits, called the alpha, beta, and phosphodiesterase (see Figure 5.7). This enzyme is also sub-
gamma subunits. The alpha subunit can bind guanosine diphos- ject to physiological control. Thus, the cellular concentration of
phate (GDP) and guanosine triphosphate (GTP). The beta and cAMP can be changed either by altering the rate of its messenger-
gamma subunits help anchor the alpha subunit in the membrane. mediated synthesis or the rate of its phosphodiesterase-mediated
The binding of a first messenger to the receptor changes the breakdown. Caffeine and theophylline, the active ingredients of
conformation of the receptor. This activated receptor increases the coffee and tea, are widely consumed stimulants that work partly
affinity of the alpha subunit of the G protein for GTP. When bound by inhibiting cAMP phosphodiesterase activity, thereby prolong-
to GTP, the alpha subunit dissociates from the beta and gamma ing the actions of cAMP within cells. In many cells, such as those
subunits of the trimeric G protein. This dissociation allows the of the heart, an increased concentration of cAMP triggers an
activated alpha subunit to link up with still another plasma mem- increase in function (for example, an increase in heart rate).
brane protein, either an ion channel or an enzyme. These ion What does cAMP actually do inside the cell? It binds to and
channels and enzymes are effector proteins that mediate the next activates an enzyme known as cAMP-dependent protein kinase,
steps in the sequence of events leading to the cell’s response. also called protein kinase A (see Figure 5.6). Recall that protein
In essence, then, a G protein serves as a switch to couple a kinases phosphorylate other proteins—often enzymes—by trans-
receptor to an ion channel or to an enzyme in the plasma mem- ferring a phosphate group to them. The changes in the activity of
brane. Consequently, these receptors are known as G-protein- proteins phosphorylated by cAMP-dependent protein kinase bring
coupled receptors. The G protein may cause the ion channel to about a cell’s response (secretion, contraction, and so on). Again,
open, with a resulting change in electrical signals or, in the case recall that each of the various protein kinases that participate in the
of Ca2+ channels, changes in the cytosolic Ca2+ concentration. multiple signal transduction pathways described in this chapter has
Alternatively, the G protein may activate or inhibit the membrane its own specific substrates.
enzyme with which it interacts. Such enzymes, when activated, In essence, then, the activation of adenylyl cyclase by the
cause the generation of second messengers inside the cell. Gs protein initiates an “amplification cascade” of events that con-
Once the alpha subunit of the G protein activates its effector verts proteins in sequence from inactive to active forms. Figure 5.8
protein, a GTPase activity inherent in the alpha subunit cleaves the illustrates the benefit of such a cascade. While it is active, a single
GTP into GDP and Pi. This cleavage renders the alpha subunit inac- enzyme molecule is capable of transforming into product not one but
tive, allowing it to recombine with its beta and gamma subunits. many substrate molecules, let us say 100. Therefore, one active mol-
There are several subfamilies of plasma membrane G pro- ecule of adenylyl cyclase may catalyze the generation of 100 cAMP
teins, each with multiple distinct members, and a single receptor molecules (and thus 100 activated cAMP-dependent protein kinase
126 Chapter 5
 Extracellular fluid
Begin First
messenger

GDP GTP Plasma membrane

Adenylyl
Receptor
β
α α cyclase

γ β
γ
Gs Protein
Second Intracellular fluid
messenger
ATP cAMP

Figure 5.6 Inactive Active

Cyclic AMP second- cAMP-dependent cAMP-dependent
messenger system. Not protein kinase protein kinase
shown in the figure is
the existence of another
regulatory protein, Gi, Protein + ATP Protein-PO4 + ADP
which certain receptors
can react with to cause
inhibition of adenylyl CELL’S RESPONSE
cyclase.

O O O
A molecules). At each of the two subsequent enzyme-activation steps
in our example, another 100-fold amplification occurs. Therefore,
HO P O P O P O CH2 Adenine the end result is that a single molecule of the first messenger could,
OH OH OH O in this example, cause the generation of 1 million product molecules.
H H
This helps to explain how hormones and other messengers can be
ATP
H H effective at extremely low extracellular concentrations. To take an
OH OH actual example, one molecule of the hormone epinephrine can cause
Adenylyl cyclase the liver to generate and release 108 molecules of glucose.
In addition, activated cAMP-dependent protein kinase
can diffuse into the cell nucleus, where it can phosphorylate a
PP protein that then binds to specific regulatory regions of certain
genes. Such genes are said to be cAMP-responsive. Therefore,
O CH2 Adenine
the effects of cAMP can be rapid and independent of changes
O in gene activity, as in the example of epinephrine and glucose
cAMP
H H production, or slower and dependent upon the formation of new
H H gene products.
H2O
O P O OH How can cAMP’s activation of a single molecule, cAMP-
dependent protein kinase, be common to the great variety of
OH
biochemical sequences and cell responses initiated by cAMP-
cAMP phosphodiesterase
generating first messengers? The answer is that cAMP-dependent
protein kinase can phosphorylate a large number of different pro-
teins (Figure 5.9). In this way, activated cAMP-dependent protein
O
AMP kinase can exert multiple actions within a single cell and different
HO P O CH2 Adenine actions in different cells. For example, epinephrine acts via the
OH O cAMP pathway on adipose cells to stimulate the breakdown of tri-
glyceride, a process that is mediated by one particular phosphor-
H H
H H ylated enzyme that is chiefly expressed in adipose cells. In the
OH OH
liver, epinephrine acts via cAMP to stimulate both the breakdown
of glycogen and the synthesis of glucose, processes that are medi-
Figure 5.7 Formation and breakdown of cAMP. ATP is converted to ated by phosphorylated enzymes that differ from those expressed
cAMP by the action of the plasma membrane enzyme adenylyl cyclase. in adipose cells.
cAMP is inactivated by the cytosolic enzyme cAMP phosphodiesterase, Whereas phosphorylation mediated by cAMP-dependent
which converts cAMP into the noncyclized form AMP. protein kinase activates certain enzymes, it inhibits others. For
Cell Signaling in Physiology 127
 Ion
Active channel Plasma
transport
membrane
First
messenger ATP

Number of
molecules ADP

cAMP-dependent
Receptor 1 protein kinase Endoplasmic reticulum
Protein synthesis;
Ca2+ transport

Microtubules
DNA
Transport; secretion;
cell shape changes
Enzyme 1 Enzyme 2 mRNA
100
cAMP

Lipid Glycogen Nucleus

breakdown breakdown

cAMP- cAMP- cAMP- cAMP-

dependent dependent dependent dependent 100
protein kinase protein kinase protein kinase protein kinase

(each kinase phosphorylates 100 enzymes)

Figure 5.9 The variety of cellular responses induced by

Phosphorylated enzyme cAMP is due mainly to the fact that activated cAMP-dependent
protein kinase can phosphorylate many different proteins, activating
Enzyme Enzyme Enzyme Enzyme 10,000 or inhibiting them. In this figure, the protein kinase is shown
phosphorylating seven different proteins—a microtubular protein,
(each enzyme phosphorylates 100 final products)
an ATPase, an ion channel, a protein in the endoplasmic reticulum,
a protein involved in stimulating the transcription of a gene into
mRNA, and two enzymes.
1,000,000

Phosphorylated final products DIG DEEPER

■ Does a given protein kinase, such as cAMP-dependent protein
Figure 5.8 Example of signal amplification. In this kinase, phosphorylate only the same proteins in all cells in which
example, a single molecule of a first messenger results in the kinase is present?
1 million final products. Other second-messenger pathways have
similar amplification processes. The steps between receptor activation Answer found in Appendix A.
and cAMP generation are omitted for simplicity.

DIG DEEPER associated with a different G protein known as Gi (the subscript

i denotes “inhibitory”). Activation of Gi causes the inhibition of
■ What are the advantages of having an enzyme (like adenylyl cyclase)
involved in the initial response to receptor activation by a first adenylyl cyclase. The result is to decrease the concentration of
messenger? (Hint: Recall one of the key characteristics of enzymes cAMP in the cell and thereby the phosphorylation of key proteins
described in Sections 3.11–3.13 of Chapter 3. Does a given activated inside the cell.
enzyme catalyze a reaction only once, or can it act many times?) Many cells express both stimulatory and inhibitory G pro-
teins in their membranes, providing a means of tightly regulat-
Answer found in Appendix A.
ing intracellular cAMP concentrations. This common cellular
feature highlights the general principle of physiology that most
physiological functions are controlled by multiple regulatory sys-
example, the enzyme catalyzing the rate-limiting step in glycogen tems, often working in opposition. It provides for fine-tuning of
synthesis is inhibited by phosphorylation. This explains how in the cellular responses and, in some cases, the ability to override a
liver epinephrine inhibits glycogen synthesis at the same time it response.
stimulates glycogen breakdown by activating the enzyme that cata- Finally, as indicated in Figure 5.9, cAMP-dependent protein
lyzes the latter response. kinase can phosphorylate certain plasma membrane ion chan-
Not mentioned thus far is the fact that receptors for some nels, thereby causing them to open or in some cases to close. As
first messengers, upon activation by their messengers, inhibit we have seen, the sequence of events leading to the activation of
adenylyl cyclase. This inhibition results in less, rather than more, cAMP-dependent protein kinase proceeds through a G protein, so
generation of cAMP. This occurs because these receptors are it should be clear that the opening of such channels is indirectly
128 Chapter 5
 DAG activates members of a family of related protein kinases
Summary of Common Mechanisms by
known collectively as protein kinase C, which, in a fashion simi-
TABLE 5.2 Which Receptor Activation Influences Ion
Channels lar to cAMP-dependent protein kinase, then phosphorylates a large
number of other proteins, leading to the cell’s response.
The ion channel is part of the receptor. IP3, in contrast to DAG, does not exert its second-
messenger function by directly activating a protein kinase.
A G protein directly gates the ion channel. Rather, cytosolic IP3 binds to receptors located on the endoplas-
mic reticulum. These receptors are ligand-gated Ca 2+ channels
A G protein gates the ion channel indirectly via production of a that open when bound to IP3. Because the concentration of Ca 2+
second messenger such as cAMP.
is much greater in the endoplasmic reticulum than in the cytosol,
Ca 2+ diffuses out of this organelle into the cytosol, significantly
dependent on that G protein. This is distinct from the direct increasing the cytosolic Ca 2+ concentration. This increased
action of a G protein on an ion channel, mentioned earlier. To Ca 2+ concentration then continues the sequence of events lead-
generalize, the indirect G-protein gating of ion channels utilizes ing to the cell’s response to the first messenger. We will pick up
a ­second-messenger pathway for the opening or closing of the this thread in more detail shortly. However, it is worth noting
channel. Table 5.2 summarizes the three ways by which receptor that one of the actions of Ca 2+ is to help activate some forms
activation by a first messenger leads to opening or closing of ion of protein kinase C (which is how this kinase got its name—C
channels, causing a change in membrane potential. for “calcium”).

Phospholipase C, Diacylglycerol, and Inositol Ca2+

Trisphosphate The calcium ion functions as a second messenger in a great vari-
In this system, a G protein called Gq is activated by a receptor ety of cellular responses to stimuli, both chemical and electrical.
bound to a first messenger. Activated Gq then activates a plasma The physiology of Ca2+ as a second messenger requires an analy-
membrane effector enzyme called phospholipase C. This enzyme sis of two broad questions: (1) How do stimuli cause the cytosolic
catalyzes the breakdown of a plasma membrane phospholipid Ca2+ concentration to increase? (2) How does the increased Ca2+
known as phosphatidylinositol bisphosphate, abbreviated PIP2, concentration elicit the cells’ responses?
to diacylglycerol (DAG) and inositol trisphosphate (IP 3) By means of active-transport systems in the plasma
(Figure 5.10). Both DAG and IP3 then function as second mes- membrane and membranes of certain cell organelles, Ca 2+ is
sengers but in very different ways. maintained at an extremely low concentration in the cytosol.

Extracellular fluid

First Second
messenger messengers

PIP2 IP3 + DAG

Plasma membrane
GDP GTP
Receptor α α Phospholipase C
β
γ
β
Gq Protein γ
Ca2+ Intracellular
Ca2+ fluid
Ca2+ Inactive protein Active protein
kinase C kinase C
IP3 receptor IP3

Endoplasmic
reticulum

Calcium ions Protein + ATP Protein-PO4 + ADP

CELL’S RESPONSE

CELL’S RESPONSE

Figure 5.10 Mechanism by which an activated receptor stimulates the enzymatically mediated breakdown of PIP2 to yield IP3 and DAG. IP3
then binds to a receptor on the endoplasmic receptor. This receptor is a ligand-gated ion channel that, when opened, allows the release of Ca2+ from the
endoplasmic reticulum into the cytosol. Together with DAG, Ca2+ activates protein kinase C.
Cell Signaling in Physiology 129
 TABLE 5.3 Ca2+ as a Second Messenger Begin Extracellular fluid
First
Common Mechanisms by Which Stimulation of a Cell Leads to messenger
an Increase in Cytosolic Ca2+ Concentration

I. Receptor activation
Plasma membrane
A. Plasma-membrane Ca2+ channels open in response to a first
Receptor
messenger; the receptor itself may contain the channel, or
the receptor may activate a G protein that opens the channel
via a second messenger.
Intracellular fluid
B. Ca2+ is released from the endoplasmic reticulum; this is
typically mediated by IP3.
C. Active Ca2+ transport out of the cell is inhibited by a second
messenger. Ca2+ entry via plasma membrane Ca2+ channels
II. Opening of voltage-gated Ca2+ channels and/or
Ca2+ release from endoplasmic reticulum
Major Mechanisms by Which an Increase in Cytosolic Ca2+
Concentration Induces the Cell’s Responses
Second
2+ 2+
Cytosolic Ca2+ messenger
I. Ca binds to calmodulin. On binding Ca , the calmodulin
changes shape and becomes activated, which allows it to
activate or inhibit a large variety of enzymes and other proteins. Inactive Active Ca2+–
calmodulin calmodulin
Many of these enzymes are protein kinases.
II. Ca2+ combines with Ca2+-binding proteins other than
calmodulin, altering their functions.
Inactive Active
calmodulin-dependent calmodulin-dependent
protein kinase protein kinase
Consequently, there is always a large electrochemical gradient
favoring diffusion of Ca 2+ into the cytosol via Ca 2+ channels
found in both the plasma membrane and, as mentioned earlier,
the endoplasmic reticulum. A stimulus to the cell can alter this Protein + ATP Protein–PO4 + ADP
steady state by influencing the active-transport systems and/or
the ion channels, resulting in a change in cytosolic Ca 2+ con-
centration. The most common ways that receptor activation by CELL’S RESPONSE
a first messenger increases the cytosolic Ca 2+ concentration
have, in part, been presented in this chapter and are summa- Figure 5.11 Ca2+, calmodulin, and the calmodulin-dependent
rized in the top part of Table 5.3. protein kinase system. (There are multiple calmodulin-dependent
Now we turn to the question of how the increased cytosolic protein kinases.) Table 5.3 summarizes the mechanisms for increasing
Ca2+ concentration elicits the cells’ responses (see bottom of cytosolic Ca2+ concentration.
Table 5.3). The common denominator of Ca2+ actions is its ability to
bind to various cytosolic proteins, altering their conformation and
thereby activating their function. One of the most important of these produced from the polyunsaturated fatty acid arachidonic acid,
is a protein found in all cells known as calmodulin (Figure 5.11). which is present in plasma membrane phospholipids. The eico-
On binding with Ca2+, calmodulin changes shape, and this allows sanoids include the cyclic endoperoxides, the prostaglandins, the
Ca2+–calmodulin to activate or inhibit a large variety of enzymes thromboxanes, and the leukotrienes (Figure 5.12). They are gen-
and other proteins, many of them protein kinases. Activation or erated in many kinds of cells in response to different types of extra-
inhibition of these calmodulin-dependent protein kinases leads, cellular signals; these include a variety of growth factors, immune
via phosphorylation, to activation or inhibition of proteins involved defense molecules, and even other eicosanoids. Thus, eicosanoids
in the cell’s ultimate responses to the first messenger. may act as both extracellular and intracellular messengers, depend-
Calmodulin is not, however, the only intracellular protein ing on the cell type.
influenced by Ca2+ binding. For example, you will learn in Chap- The synthesis of eicosanoids begins when an appropriate
ter 9 how Ca2+ binds to a protein called troponin in certain types stimulus—hormone, neurotransmitter, paracrine substance, drug,
of muscle to initiate contraction. or toxic agent—binds its receptor and activates phospholipase A2,
Finally, for reference purposes, Table 5.4 summarizes an enzyme localized to the plasma membrane of the stimulated
the production and functions of the major second messengers cell. As shown in Figure 5.12, this enzyme splits off arachidonic
described in this chapter. acid from the membrane phospholipids, and the arachidonic acid
can then be metabolized by two pathways. One pathway is ini-
Other Messengers tiated by an enzyme called cyclooxygenase (COX) and leads
In a few places in this text, you will learn about messengers that ultimately to formation of the cyclic endoperoxides, prostaglan-
are not as readily classified as those just described. Among these dins, and thromboxanes. The other pathway is initiated by the
are the eicosanoids. The eicosanoids are a family of molecules enzyme lipoxygenase and leads to formation of the leukotrienes.
130 Chapter 5
 TABLE 5.4 Reference Table of Important Second Messengers
Substance Source Effects

Ca2+ Enters cell through plasma membrane ion channels or is Activates protein kinase C, calmodulin, and
released into the cytosol from endoplasmic reticulum. other Ca 2+-binding proteins; Ca 2+ –calmodulin
activates calmodulin-dependent protein
kinases.

Cyclic AMP (cAMP) A G protein activates plasma membrane adenylyl cyclase, Activates cAMP-dependent protein kinase
which catalyzes the formation of cAMP from ATP. (protein kinase A).

Cyclic GMP (cGMP) Generated from guanosine triphosphate in a reaction Activates cGMP-dependent protein kinase
catalyzed by a plasma membrane receptor with guanylyl (protein kinase G).
cyclase activity.

Diacylglycerol (DAG) A G protein activates plasma membrane phospholipase Activates protein kinase C.
C, which catalyzes the generation of DAG and IP3 from
plasma membrane phosphatidylinositol bisphosphate
(PIP2).

Inositol trisphosphate (IP3) See DAG above. Releases Ca2+ from endoplasmic reticulum into
the cytosol.

Begin
First
messenger

Membrane phospholipid
Receptor Phospholipase A2

Arachidonic acid

Figure 5.12 Pathways for eicosanoid synthesis and some of their

major functions. Phospholipase A2 is the one enzyme common to
Cyclooxygenase
pathway
the formation of all the eicosanoids. Anti-inflammatory steroids
Lipoxygenase
induce expression of a protein that inhibits phospholipase A2. The
Cyclic endoperoxides pathway pathway mediated by cyclooxygenase is inhibited by aspirin and other
nonsteroidal anti-inflammatory drugs (NSAIDs). There are also drugs
available that inhibit the lipoxygenase enzyme, thereby blocking the
formation of leukotrienes. These drugs may be helpful in controlling
asthma, in which excess leukotrienes have been implicated in the
allergic and inflammatory components of the disease.
Prostaglandins Thromboxanes
Leukotrienes DIG DEEPER
Vascular actions, Blood clotting ■ Based on the pathways shown in this figure, propose a reason for
inflammation and other why people are advised to avoid taking aspirin or other NSAIDs
vascular actions prior to a surgical procedure.
Mediate allergic and Answer found in Appendix A.
inflammatory reactions

Within both of these pathways, synthesis of the various specific structural differences, the different molecules within each subdi-
eicosanoids is enzyme-mediated. Thus, beyond phospholipase A2, vision are designated by a letter—for example, PGA and PGE for
the eicosanoid-pathway enzymes expressed in a particular cell prostaglandins of the A and E types, which then may be further
determine which eicosanoids the cell synthesizes in response to ­subdivided—for example, PGE2.
a stimulus. Once they have been synthesized in response to a stimu-
Each of the major eicosanoid subdivisions contains more lus, the eicosanoids may in some cases act as intracellular mes-
than one member, as indicated by the use of the plural in refer- sengers, but more often they are released immediately and act
ring to them (prostaglandins, for example). On the basis of locally. For this reason, the eicosanoids are usually categorized
Cell Signaling in Physiology 131
as paracrine and autocrine substances. After they act, they are the various signal transduction pathways. For example, active
quickly metabolized by local enzymes to inactive forms. The molecules generated in the cAMP pathway can alter the activ-
eicosanoids exert a wide array of effects, particularly on blood ity of receptors and signaling molecules generated by other
vessels and in inflammation. Many of these will be described in pathways.
future chapters.
Certain drugs influence the eicosanoid pathway and are St udy and Review 5.2
among the most commonly used in the world today. Aspirin, for
example, inhibits cyclooxygenase and, therefore, blocks the syn- ■ Receptor activation: initial step leading to a cell’s response
thesis of the endoperoxides, prostaglandins, and thromboxanes. It to a messenger; occurs due to a conformational change in the
and other drugs that also block cyclooxygenase are collectively receptor triggered by its binding a messenger
termed nonsteroidal anti-inflammatory drugs (NSAIDs). Their ■ Signal transduction pathways: the diverse sequences of
major uses are to reduce pain, fever, and inflammation. The term events that link receptor activation to a cell’s ultimate response
nonsteroidal distinguishes them from synthetic glucocorticoids to a messenger
(analogs of steroid hormones made by the adrenal glands) that are
■ Lipid-soluble messengers: bind to nuclear receptors inside
used in large doses as anti-inflammatory drugs. These steroids
the target cell
induce expression of a protein that inhibits phospholipase A2.
∙∙ The activated receptor acts in the nucleus as a transcription
Therefore, these steroids block the production of all eicosanoids.
factor.
Water-soluble messengers: bind to four classes of receptors on
Cessation of Activity in Signal Transduction ■
the plasma membrane:
Pathways ∙∙ receptors that are also ligand-gated ion channels
Responses to messengers are often transient events that persist ∙∙ receptors that are also enzymes
only briefly and subside when the receptor is no longer bound to ∙∙ receptors that activate a cytosolic janus kinase associated
the first messenger. There are numerous ways in which this may with them
occur. For example, the first messenger may be metabolized by ∙∙ receptors that interact with an associated plasma membrane
enzymes in its vicinity, or be taken up by cells and destroyed, or G protein (G-protein-coupled receptors)
it may simply diffuse away. When events such as these happen,
■ First messengers: the messengers that bind to cell receptors
the rate of second-messenger production decreases. The intracel-
lular concentration of second messenger will then decrease due ■ Second messengers: substances generated in a cell by the
to the actions of cytosolic breakdown enzymes such as cAMP- action of first messengers
phosphodiesterase, described earlier. The importance of these ■ Adenylyl cyclase: membrane enzyme that catalyzes formation
events is to prevent chronic overstimulation of a cell by a mes- of the second messenger cAMP
senger, which can be very detrimental. ∙∙ cAMP activates intracellular cAMP-dependent protein
In addition to the removal of a first messenger, the recep- kinase, which phosphorylates proteins that mediate the cell’s
tors can be inactivated in at least three other ways: responses to the first messenger.
■■ The receptor becomes chemically altered (usually by ■ Phospholipase C: plasma membrane enzyme that catalyzes
phosphorylation), which may decrease its affinity for a formation of the second messengers diacylglycerol (DAG) and
first messenger, and so the messenger is released from its inositol trisphosphate (IP3)
receptor. ∙∙ DAG activates protein kinase C; IP3 causes release of Ca2+ from
■■ Phosphorylation of the receptor may prevent further the endoplasmic reticulum, thereby elevating cytosolic Ca2+.
G-protein binding to the receptor. ■ Ca2+ is a widespread second messenger and activates
■■ Plasma membrane receptors may be removed when the regulatory molecules such as calmodulin.
combination of first messenger and receptor is taken into
■ Eicosanoids: derived from arachidonic acid, and exert
the cell by endocytosis.
widespread intracellular and extracellular effects on cell
The processes described here are physiologically controlled. For activity
example, in many cases the inhibitory phosphorylation of a recep- ∙∙ examples include prostaglandins, thromboxanes, and
tor is mediated by a protein kinase that was initially activated in leukotrienes
response to the first messenger. This receptor inactivation consti- ■ Cessation of receptor activity occurs when the first-messenger
tutes negative feedback. molecule concentration decreases or, in the case of plasma
This concludes our description of the basic principles membrane receptors, when the receptor is chemically altered or
of signal transduction pathways. It is essential to recognize internalized.
that the pathways do not exist in isolation but may be active
Review Question: A newly discovered chemical messenger is
simultaneously in a single cell, undergoing complex interac- observed to be poorly soluble in water but freely soluble in lipid
tions. This is possible because a single first messenger may (oil). What class of messenger might this be? Would you expect it
trigger changes in the activity of more than one pathway and, to exert its effects faster than, slower than, or at about the same
much more importantly, because many different first messen- rate as a messenger that results in synthesis of cAMP? (Answer
gers may simultaneously influence a cell. Moreover, a great found in Appendix A.)
deal of “cross talk” can occur at one or more levels among
132 Chapter 5
CHAPTER 5 Clinical Case Study: A
 Child with Unexplained Weight Gain
and Calcium Imbalance
A 3-year-old girl was seen by her pedia- bones and kidneys—to maintain Ca2+ balance in the blood. What
trician to determine the cause of a recent could prevent PTH from doing its job? How might this be related to
increase in the rate of her weight gain. Her the thyroid hormone imbalance that was responsible for the weight
height was normal (95 cm/37.4 inches), but gain?
she weighed 16.5 kg (36.3 pounds), which A genetic condition in which the PTH concentration in the
is in the 92nd percentile for her age. The blood is high but Ca2+ is low is pseudohypoparathyroidism. The
girl’s mother—who was very short and prefix hypo in this context refers to “less than normal amounts of”
overweight—stated that the child seemed PTH in the blood. This girl’s condition seemed to fit a diagnosis of
Comstock Images/Getty Images listless at times and was rarely very active. hypoparathyroidism, because her Ca2+ concentration was low and
She was also prone to muscle cramps and she consequently demonstrated several symptoms characteristic of
complained to her mother that her fingers low Ca2+. These findings would suggest that there was not enough
and toes “felt funny,” which the pediatrician was able to interpret PTH available. However, because her PTH concentration was not
as tingling sensations. She had a good appetite but not one that low—in fact, it was higher than normal—the condition is called
appeared unusual or extreme. The doctor suspected that the child pseudo, or “false,” hypoparathyroidism.
had developed a deficiency in the amount of thyroid hormone in her A blood sample was taken from the girl and the white blood
blood. This hormone is produced by the thyroid gland in the neck cells were subjected to DNA analysis to test the possibility that a
(look ahead to Figure 11.21) and is responsible in part for normal mutation might exist in a gene required for PTH signaling.
metabolism—that is, the rate at which calories are expended. Too
Reflect and Review #2
little thyroid hormone typically results in weight gain and may also
■■ What is a mutation, and how might it result in a change in the
cause fatigue or lack of energy. A blood test was performed, and
primary structure of a protein? (Refer back to Figures 2.16
indeed the girl’s thyroid hormone concentration was low. Because
and 2.17 for help.)
there are several conditions that may result in a deficiency of thyroid
hormone, an additional exam was performed. During that exam, the That analysis revealed that the girl was heterozygous for a
physician noticed that the fourth metacarpals (the bones at the base mutation in the GNAS1 gene, which encodes the alpha subunit of
of the ring fingers) on each of the girl’s hands were shorter than nor- the stimulatory G protein (Gs alpha). Recall from Figure 5.6 that Gs
mal, and he could feel hard bumps (nodules) just beneath the girl’s couples certain plasma membrane receptors to adenylyl cyclase and
skin at various sites on her body. He ordered a blood test for Ca2+ the production of cAMP, an important second messenger in many
and for a hormone called parathyroid hormone (PTH). cells. PTH is known to act by binding to a plasma membrane receptor
PTH gets its name because the glands that produce it and activating adenylyl cyclase via this pathway. Because the girl had
lie adjacent (para) to the thyroid gland. PTH normally acts on decreased expression of normal Gs alpha, her cells were unable to
the kidneys and bones to maintain calcium ion homeostasis in respond adequately to PTH, and consequently her blood concentra-
the blood. tion of Ca2+ could not be maintained within the normal range, even
though she was not deficient in PTH.
Reflect and Review #1
PTH, however, is not the only messenger in the body that
■■ In what general ways is balance of Ca2+ achieved in the
acts through a G s -coupled receptor linked to cAMP production.
blood? (Refer back to Section 1.8 of Chapter 1 for help.)
As you have learned in this chapter, there are many other such
Should the Ca2+ concentration in the blood decrease for any molecules. One of them is a factor that stimulates thyroid hor-
reason, PTH secretion will increase and stimulate the release of mone production by the thyroid gland. This explains why the
Ca2+ from bones into the blood. It also stimulates the retention of young girl had a low thyroid hormone concentration in addition to
Ca2+ by the kidneys, such that less Ca2+ is lost in the urine. These her PTH/Ca2+ imbalance.
two factors help to restore a normal blood Ca2+ concentration—a Pseudohypoparathyroidism is a very rare disorder, but it illus-
classic example of homeostasis. The doctor suspected that the nod- trates a larger and extremely important medical concern called
ules he felt were Ca2+ deposits and that the shortened fingers were ­target-organ resistance. Such diseases are characterized by normal
the result of improper bone formation during development due to or even increased blood concentrations of signaling molecules such
a Ca2+ imbalance. Abnormally low blood Ca2+ would also explain as PTH, but also by insensitivity (that is, resistance) of a target organ
the muscle cramps and the tingling sensations. This is because a (or organs) to the molecule (Table 5.5). In our patient, the cause of
homeostatic extracellular Ca2+ concentration is also critical for nor- the resistance was insufficient Gs-alpha action due to an inherited
mal function of muscles and nerves. The results of the blood test mutation; in other cases, it may result from defects in other aspects
confirmed that the Ca2+ concentration was lower than normal. A of cell signaling pathways or in receptor structure. It is likely that the
logical explanation for why Ca2+ may be low would be because PTH girl inherited the mutation from her mother, who showed some similar
concentrations were low. Paradoxically, however, the PTH concen- symptoms.
tration was increased in the girl’s blood. This means that plenty of
PTH was present but was somehow unable to act on its targets—the
—Continued next page

Cell Signaling in Physiology 133

—Continued
Mechanisms Leading to Target-Organ
The girl was treated with a thyroid hormone pill each day, TABLE 5.5 Resistance to Chemical Messengers Such
calcium tablets twice per day, and a derivative of vitamin D (which as PTH
helps the intestines absorb Ca2+) twice per day. She will need to
Signaling
remain on this treatment plan for the rest of her life. In addition, it Receptor for Pathway Activated Is There
will be important for her physician to monitor other physiological Messenger Messenger (e.g., by Messenger Target-Organ
functions mediated by other chemical messengers that are known (e.g., PTH) PTH Receptor) (e.g., cAMP) Resistance?
to act via Gs alpha.
Present Present Present No

Missing/
Present Abnormal Present Yes

Yes (this case

Present Present Missing/Abnormal study)

See Chapter 19 for complete, integrative case studies.

cyclic endoperoxides nonsteroidal anti-inflammatory

K EY A N D CL INICA L T ER M S cyclic GMP (cGMP) drugs (NSAIDs)
cyclooxygenase (COX) nuclear receptors
5.1 Receptors
diacylglycerol (DAG) phospholipase A2
affinity oxymetazoline eicosanoids phospholipase C
agonists phenylephrine first messengers prostaglandins
antagonist receptors G-protein-coupled receptors protein kinase
antihistamines saturation G proteins protein kinase C
beta-adrenergic receptor blocker signal transduction guanylyl cyclase receptor activation
competition specificity inositol trisphosphate (IP3) receptor tyrosine kinases
down-regulation up-regulation janus kinases (JAKs) second messengers
internalization leukotrienes signal transduction pathways
lipoxygenase thromboxanes
5.2 Signal Transduction Pathways
adenylyl cyclase cAMP-dependent protein Clinical Case Study
aspirin kinase pseudohypoparathyroidism
calmodulin cAMP phosphodiesterase
calmodulin-dependent protein cGMP-dependent protein kinase
kinases cyclic AMP (cAMP)

CHAPTER 5 TEST QU E ST ION S Recall and Comprehend Answers appear in Appendix A.

These questions test your recall of important details covered in this chapter. They also help prepare you for the type of questions
encountered in standardized exams. Many additional questions of this type are available on Connect and LearnSmart.

1–3: Match a receptor feature (a–e) with each choice. 5. Which is correct?
1. Defines the situation when all receptor binding sites are occupied by a a. cAMP-dependent protein kinase phosphorylates tyrosine residues.
messenger b. Protein kinase C is activated by cAMP.
c. The subunit of Gs proteins that activates adenylyl cyclase is the beta subunit.
2. Defines the strength of receptor binding to a messenger d. Lipid-soluble messengers typically act on receptors in the cell cytosol or
3. Reflects the fact that a receptor normally binds only to a single messenger nucleus.
Receptor feature: e. The binding site of a typical plasma membrane receptor for its
a. affinity d. down-regulation messenger is located on the cytosolic surface of the receptor.
b. saturation e. specificity 6. Inhibition of which enzyme/enzymes would inhibit the conversion of
c. competition arachidonic acid to leukotrienes?
4. Which of the following intracellular or plasma membrane proteins requires a. cyclooxygenase d. adenylyl cyclase
Ca2+ for full activity? b. lipoxygenase e. both b and c
a. calmodulin c. cAMP-dependent protein kinase c. phospholipase A2
b. janus kinase (JAK) d. guanylyl cyclase

134 Chapter 5
7–10: Match each type of molecule with the correct choice (a–e); a given choice Choices:
may be used once, more than once, or not at all. a. neurotransmitter or hormone
Molecule: b. cAMP-dependent protein kinase
7. second messenger c. calmodulin
8. example of a first messenger d. Ca2+
9. part of a trimeric protein in membranes e. alpha subunit of G proteins
10. enzyme

CHAPTER 5 T E ST QU E ST I ONS Apply, Analyze, and Evaluate Answers appear in Appendix A.

These questions, which are designed to be challenging, require you to integrate concepts covered in the chapter to draw your own
conclusions. See if you can first answer the questions without using the hints that are provided; then, if you are having difficulty, refer
back to the figures or sections indicated in the hints.

1. Patient A is given a drug that blocks the synthesis of all eicosanoids, 3. A particular hormone is known to elicit—completely by way of the cyclic
whereas patient B is given a drug that blocks the synthesis of leukotrienes AMP system—six different responses in its target cell. A drug is found
but none of the other eicosanoids. What enzymes do these drugs most likely that eliminates one of these responses but not the other five. Which of the
block? Hint: Refer back to the pathways covered in Figure 5.12. following, if any, could the drug be blocking: the hormone’s receptors, Gs
2. Certain nerves to the heart release the neurotransmitter norepinephrine. protein, adenylyl cyclase, or cyclic AMP? Hint: The cAMP pathway is
If these nerves are removed in experimental animals, the heart becomes covered in Figure 5.6.
extremely sensitive to the administration of a drug that is an agonist 4. If a drug were found that blocked all Ca2+ channels that were directly
of norepinephrine. Explain why this may happen, in terms of receptor linked to G proteins, would this eliminate the function of Ca2+ as a second
physiology. Hint: See “Regulation of Receptors” in Section 5.1. messenger? Why or why not? Hint: Refer to Table 5.3 for help.

CHAPTER 5 T E ST QU E ST I ONS General Principles Assessment Answers appear in Appendix A.

These questions reinforce the key theme first introduced in Chapter 1, that general principles of physiology can be applied across all
levels of organization and across all organ systems.

1. What examples from this chapter demonstrate the general principle 2. Another general principle of physiology states that physiological processes
of physiology that controlled exchange of materials occurs between require the transfer and balance of matter and energy. How is energy
compartments and across cell membranes? Specifically, how is this related balance related to intracellular signaling?
to another general principle of physiology—namely, information flow
between cells, tissues, and organs is an essential feature of homeostasis
and allows for integration of physiological processes?

Cell Signaling in Physiology 135