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phospholipase Cβ is activated by a heptahelical receptor–G-protein signal transduction pathway.PI-4,5-bisP can also be phosphorylated at the 3′ position of inositol by the enzyme

phosphatidylinositol 3′-kinase (PI 3-kinase) to form PI-3,4,5-trisP (see Fig. 11.12). PI-3,4,5-trisP (and PI-

3,4-bisP) form membrane docking sites for proteins that contain a certain sequence of amino acids called

the pleckstrin homology (PH) domain. PI 3-kinase contains an SH2 domain and is activated by binding to

a specific phosphotyrosine site on a tyrosine kinase receptor or receptor-associated protein. The protein

phosphatase and tensin homolog (PTEN) catalyzes the dephosphorylation of PI-3,4,5-trisP to PI-4,5-bisP,

thereby removing the primary signal from the pathway. Mutations within PTEN, or misexpression of

PTEN, can lead to cancer (see Chapter 18). 3. The Insulin Receptor

The insulin receptor, a member of the tyrosine kinase family of receptors, provides a good example of

divergence in the pathway of signal transduction. Unlike other growth-factor receptors, the insulinreceptor exists in the membrane as a preformed dimer, with each half containing an α- and a β-subunit

(Fig. 11.13). The β-subunits autophosphorylate each other when insulin binds, thereby activating the

receptor. The activated phosphorylated receptor binds a protein called insulin receptor substrate (IRS).

The activated receptor kinase phosphorylates IRS at multiple sites, creating multiple binding sites for

different proteins with SH2 domains. One of the sites binds the adapter protein Grb2, which leads to the

activation of Ras and the MAP kinase pathway. At another phosphotyrosine site, PI 3-kinase binds and is

activated. This pathway will lead to the activation of protein kinase B (PKB). At a third site, PLCγ binds

and is activated. The insulin receptor can also transmit signals through direct docking with other signal

transduction intermediates.

The signal pathway initiated by the insulin–receptor complex involving PI 3-kinase leads to activation

of protein kinase B (also called Akt), a serine–threonine kinase that mediates many of the downstream

effects of insulin (Fig. 11.14). PI 3-kinase binds to IRS and phosphorylates PI-4,5-bisP in the membrane

to form PI-3,4,5-trisP. Protein kinase B and phosphoinositide-dependent kinase-1 (PDK1) are recruited to

the membrane by their PH domains, where PDK1 phosphorylates and activates protein kinase B. One of

the signal transduction pathways for Akt leads to the effects of insulin on glucose metabolism. Other

pathways result in the phosphorylation of a host of other proteins that affect cell growth and survival. In

general, phosphorylation of these proteins by Akt promotes cell survival. The action of insulin is covered

in more detail in Chapters 26, 36, and 43. It is important to note that other receptors’ tyrosine kinase

receptors will also lead to the activation of the Akt pathway through the direct binding of PI 3-kinase to

activated receptors (see Section III.B.2 of this chapter).Insulin is a growth factor that is essential for cell viability and growth. It increases general

protein synthesis, which strongly affects muscle mass through hypertrophy. However, it also

regulates immediate nutrient availability and storage, including glucose transport into skeletal

muscle and glycogen synthesis. Thus, Dianne A. and other patients with type 1 diabetes mellitus

who lack insulin rapidly develop hyperglycemia once insulin levels drop too low. They also

exhibit muscle “wasting.” To mediate the diverse regulatory roles of insulin, the signal

transduction pathway diverges after activation of the receptor and phosphorylation of IRS, which

has multiple binding sites for different signal-mediator proteins.

C.Signal Transduction by Cytokine Receptors: Use of JAK-STAT Proteins Tyrosine kinase–associated receptors in the cytokine receptor family transduce signals through janus

kinase (JAK)/STAT proteins to regulate the proliferation of certain cells involved in the immune response

(see Fig. 11.9B). The receptors themselves have no intrinsic kinase activity but bind (associate with) a

tyrosine kinase of the JAK family. Their signal transducer proteins, called STATs, are themselves genespecific transcription factors. Thus, cytokine receptors use a more direct route for propagation of the

signal to the nucleus than tyrosine kinase receptors.

Each receptor monomer has an extracellular domain, a membrane-spanning region, and an

intracellular domain. As the cytokine binds to these receptors, they form dimers or trimers (either

between the same or distinct receptor molecules) and may cluster (Fig. 11.15). The activated receptorassociated tyrosine kinases phosphorylate each other on tyrosine residues and also phosphorylate tyrosine

residues on the receptor, forming phosphotyrosine-binding sites for the SH2 domain of a STAT. STATs are

inactive in the cytoplasm until they bind to the receptor complex, where they are also phosphorylated by

the bound JAK. Phosphorylation changes the conformation of the STAT, causing it to dissociate from the

receptor and dimerize with another phosphorylated STAT, thereby forming an activated transcription

factor. The STAT dimer translocates to the nucleus and binds to a response element on DNA, thereby

regulating gene transcription.There are many different STAT proteins, each with a slightly different amino acid sequence.

Receptors for different cytokines bind different STATs, which then form heterodimers in various

combinations. This microheterogeneity allows different cytokines to target different genes. STAT

signaling is regulated in several ways. Two prominent types are a protein family known as suppressors of

cytokine signaling (SOCS) and protein inhibitors of activated STAT (PIAS). Both SOCS and PIAS genes

are induced by activated STAT in order to limit the duration of the second message.

D.Receptor Serine–Threonine Kinases

Proteins in the transforming growth factor superfamily use receptors that have serine–threonine kinase

activity and associate with proteins from the Smad family, which are gene-specific transcription factors

(see Fig. 11.9C). This superfamily includes (1) transforming growth factor β (TGF-β), a

cytokine/hormone involved in tissue repair, immune regulation, and cell proliferation; and (2) bone

morphogenetic proteins (BMPs), which control proliferation, differentiation, and cell death during

development.

A simplified version of TGF-β binding to its receptor complex and activating Smads is illustrated in

Figure 11.16. The TGF-β receptor complex is composed of two different single membrane-spanning

receptor subunits (type I and type II), which have different functions even though they both have serine

kinase domains. TGF-β binds to a type II receptor. The activated type II receptor

recruits a type I

receptor, which it phosphorylates at a serine residue, forming an activated receptor complex. The type I

receptor then binds a receptor-specific Smad protein (called an R-Smad), which it phosphorylates on

serine residues. The phosphorylated R-Smad undergoes a conformational change and dissociates from the

receptor. It then forms a complex with another member of the Smad family, Smad 4 (Smad 4 is known as

the common Smad, Co-Smad, and is not phosphorylated). The Smad complex, which may contain several

Smads, translocates to the nucleus, where it activates or inhibits the transcription of target genes.

Receptors for distinct ligands bind different Smads, which bind to alternative sites on DNA and regulate

the transcription of different sets of genes. There is also an inhibitory Smad that is activated which acts to

regulate the extent of Smad activation (another example of signal termination).E. Signal Transduction through Heptahelical Receptors

The heptahelical receptors are named for their seven membrane-spanning domains, which are α-helices

(see Fig. 11.10; see also Fig. 7.9). Although hundreds of hormones and neurotransmitters work through

heptahelical receptors, the extracellular binding domain of each receptor is specific for just one

polypeptide hormone, catecholamine, or neurotransmitter (or a close structural analog). Heptahelical

receptors have no intrinsic kinase activity but initiate signal transduction through heterotrimeric Gproteins composed of α-, β-, and γ-subunits. However, different types of heptahelical receptors bind

different G-proteins, and different G-proteins exert different effects on their target proteins. The activation

of the G-protein leads to second messenger production within the cells. Second messengers are present in

low concentrations so that modulation of their level, and hence the message, can be rapidly initiated and

terminated.

ACh has two types of receptors: nicotinic ion-channel receptors (the receptors inhibited by

antibodies in myasthenia gravis) and muscarinic receptors (which exist as a variety of

subtypes). The M2 muscarinic receptors activate a Gαi/o heterotrimeric G-protein in which release

of the βγ-subunit controls K+ channels and pacemaker activity in the heart. Epinephrine has

several types and subtypes of heptahelical receptors: β-Adrenergic receptors work through a Gαs

and stimulate adenylyl cyclase, α2-adrenergic receptors in other cells work through a Gαi protein

and inhibit adenylyl cyclase, and α1-adrenergic receptors work through Gαq subunits and activate

phospholipase Cβ. This variety in receptor types allows a messenger to have different actions in

different cells.

1. Heterotrimeric G-Proteins

The function of heterotrimeric G-proteins is illustrated in Figure 11.17 using a hormone that activates

adenylyl cyclase (e.g., glucagon or epinephrine). While the α-subunit contains bound GDP, it remains

associated with the β- and γ-subunits, either free in the membrane or bound to an unoccupied receptor

(see Fig. 11.17, part 1). When the hormone binds, it causes a conformational change in the receptor that

promotes GDP dissociation and GTP binding. The exchange of GTP for bound GDP causes dissociationof the α-subunit from the receptor and from the β- and γ-subunits (see

Fig. 11.17, part 2). The α- and γ-

subunits are tethered to the intracellular side of the plasma membrane through lipid anchors, but the

subunits can still move laterally on the membrane surface. The GTP α-subunit binds its target enzyme in

the membrane, thereby changing its activity. In this example, the α-subunit binds and activates adenylyl

cyclase, thereby increasing synthesis of cAMP (see Fig. 11.17, part 3).

With time, the Gα-subunit inactivates itself by hydrolyzing its own bound GTP to GDP and inorganic

phosphate (Pi) (an intrinsic GTPase activity). This action is unrelated to the number of cAMP molecules

formed. Like the monomeric G-proteins, the α-subunit now containing GDP dissociates from its target

protein, adenylyl cyclase (see Fig. 11.17, part 4). It reforms the trimeric G-protein complex, which may

return to bind the empty hormone receptor. As a result of this GTPase “internal clock,” sustained

elevation of hormone levels is necessary for continued signal transduction and elevation of cAMP. Gproteins in which the internal clock has become defective (either through mutation or modification by

toxins) can become permanently activated, thereby continuously stimulating their signal transduction

pathway.

There are a large number of different heterotrimeric G-protein complexes which are generally

categorized according to the activity of the α-subunit (Table 11.1). The 20 or so different isoforms of Gα

fall into five broad categories: Gαs, Gαi/o, Gαt, Gαq/11, and Gα12/13. Gαs refers to α-subunits, which, like

the one in Figure 11.17, stimulate adenylyl cyclase (hence the s). Gα-subunits that inhibit adenylyl cyclase

are called Gαi. The β- and γ-subunits likewise exist as different isoforms, which also transmit messages.

Gα

qs subunits activate phospholipase Cβ, which generates second messengers based on phosphatidylinositol. Gαt subunits activate cGMP phosphodiesterase. Gα12/13 subunits activate a GEF,which activates the small GTP-binding protein Rho, which is involved in cytoskeletal alterations.

2. Adenylyl Cyclase and cAMP Phosphodiesterase

cAMP is referred to as a second messenger because changes in its concentration reflect changes in the

concentration of the hormone (the first messenger). When a hormone binds and adenylyl cyclase is

activated, it synthesizes cAMP from ATP. cAMP is hydrolyzed to AMP by cAMP phosphodiesterase,

which also resides in the plasma membrane (Fig. 11.18). The concentration of cAMP and other second

messengers is kept at very low levels in cells by balancing the activity of these two enzymes (the cyclase

and the phosphodiesterase) so that cAMP levels can change rapidly when hormone levels change. Some

hormones change the concentration of cAMP by targeting the phosphodiesterase enzyme rather than

adenylyl cyclase. For example, insulin lowers cAMP levels by causing phosphodiesterase activation.

cAMP exerts diverse effects in cells. It is an allosteric activator of protein kinase A (PKA) (see

Chapter 9, Section III.B.3), which is a serine–threonine protein kinase that phosphorylates a large number

of metabolic enzymes, thereby providing a rapid response to hormones like glucagon and epinephrine. It

is also the enzyme that phosphorylates the CFTR, activating the channel. PKA substrates also include,among many, phosphorylase kinase (regulation of glycogen degradation) and phospholamban (regulation

of cardiac contractility). The catalytic subunits of PKA also enter the nucleus and phosphorylate a genespecific transcription factor called cyclic-AMP response element-binding protein (CREB). Thus, cAMP

also activates a slower response pathway, gene transcription. In other cell types, cAMP activates ligandgated channels directly.

Some signaling pathways cross from the receptor tyrosine kinase pathway of MAP kinase activation to

CREB activation, and the heterotrimeric G-protein pathways diverge to include a route to the MAP kinase

pathway. These types of complex interconnections in signaling pathways are sometimes called hormone

cross-talk.

Dennis V. was hospitalized for dehydration resulting from cholera toxin (see Chapter 10).

The cholera toxin A-subunit was absorbed into the intestinal mucosal cells where it was

processed and complexed with adenosine diphosphate [ADP]-ribosylation factor (Arf), a small

G-protein that is normally involved in vesicular transport. Cholera A toxin is a nicotinamide

adenine dinucleotide (NAD)-glycohydrolase, which cleaves NAD and transfers the ADP-ribose

portion to other proteins. It ADP-ribosylates the Gαs subunit of heterotrimeric G-proteins, thereby

inhibiting their GTPase activity. As a consequence, they remain actively bound to adenylyl

cyclase, resulting in increased production of cAMP. The CFTR channel is activated, resulting in

secretion of chloride ion and Na+ ion into the intestinal lumen. The ion secretion is followed by

loss of water, resulting in vomiting and watery diarrhea. 3. Phosphatidylinositol Signaling by Heptahelical Receptors

Certain heptahelical receptors bind the q isoform of the Gα-subunit (Gαq), which activates the target

enzyme phospholipase Cβ (see Fig. 11.12). When it is activated, phospholipase Cβ hydrolyzes the

membrane lipid PI-4,5-bisP into two second messengers, DAG and IP3. IP3 has a binding site in the

sarcoplasmic reticulum and the endoplasmic reticulum that stimulates the release of Ca2+. Ca2+ activates

enzymes containing the calcium–calmodulin subunit, including a protein kinase. DAG, which remains in

the membrane, activates protein kinase C, which then propagates the response by phosphorylating target

proteins.

F. Changes in Response to Signals

Tissues vary in their ability to respond to a message through changes in receptor activity or number. Many

receptors contain intracellular phosphorylation sites that alter their ability to transmit signals. Receptor

number is also varied through downregulation. After a hormone binds to the receptor, the hormone–

receptor complex may be taken into the cell by the process of endocytosis in clathrin-coated pits (see

Chapter 10, Section II.C) The receptors may be degraded or recycled back to the cell surface. This

internalization of receptors decreases the number available on the surface under conditions of constant

high hormone levels when hormones occupy more of the receptors and results in decreased synthesis of

new receptors. Hence, it is called downregulation.IV. Signal Termination

Some signals, such as those that modify the metabolic responses of cells or that transmit neural impulses,

need to turn off rapidly when the hormone is no longer being produced. Other signals, such as those that

stimulate proliferation, turn off more slowly. In contrast, signals regulating differentiation may persist

throughout our lifetime. Many chronic diseases are caused by failure to terminate a response at the

appropriate time.

Signal transduction pathways can be terminated by a variety of means (Fig. 11.19). The first level of

termination is the chemical messenger itself. When the stimulus is no longer applied to the secreting cell,

the messenger is no longer secreted and existing messenger is catabolized. For example, many

polypeptide hormones such as insulin are taken up into the liver and degraded. Termination of the ACh

signal by acetylcholinesterase has already been mentioned.

Within each pathway of signal transduction, the signal may be turned off at specific steps. For

example, serpentine receptors can be desensitized to the messenger by phosphorylation, internalization,

and degradation. G-proteins, both monomeric and heterotrimeric, automatically terminate messages as

they hydrolyze GTP via their intrinsic GTPase activity. Although G-proteins do have intrinsic GTPase

activity, this activity is relatively weak and can be accelerated through interaction with a class of proteins

known as GTPase-activating proteins (GAPs). Termination also can be achieved through degradation of

the second messenger (e.g., phosphodiesterase cleavage of cAMP). Each of these terminating processes is

also highly regulated.

Another important pathway for reversing the message typically used by receptor kinase pathways is

through protein phosphatases, enzymes that reverse the action of kinases by removing phosphate groups

from proteins. These are specific tyrosine or serine–threonine phosphatases (enzymes that remove the

phosphate group from specific proteins) for all of the sites that are phosphorylated by signal transduction

kinases. There are even receptors that are protein phosphatases.

CLINICAL COM M ENTSMia S. Mia S. has myasthenia gravis, an autoimmune disease caused by the production of

antibodies affecting the neuromuscular junction. These antibodies are directed against the nicotinic

ACh receptor in skeletal muscles in about 85% of patients. In about 10% to 15% of patients, the

antibodies are directed against other proteins in the neuromuscular junction. The diagnosis is made by

history (presence of typical muscular symptoms), physical examination (presence of inability to do

specific repetitive muscular activity over time), and the presence of antibodies against ACh receptors.

The diagnosis can be further confirmed by neurophysiologic testing, including a diagnostic procedure

involving repetitive electrical nerve stimulation and an electromyogram (EMG) showing a partial

blockade of ion flux across muscular membranes. The prognosis for this otherwise debilitating disease

has improved dramatically with the advent of new therapies. Virtually all myasthenia patients can live

full, productive lives with proper treatment. These therapies include anticholinesterase agents;

immunosuppressive drugs, such as glucocorticoids, azathioprine, or mycophenolate; thymectomy (removal

of the thymus gland, which offers long-term benefit that may eliminate the need for a continuing medical

therapy by reducing immunoreactivity); intravenous immunoglobulin (IVIG; which

decreases the effect the

effect of autoantibodies); and plasmapheresis (which reduces anti-ACh receptor antibody levels). IVIG

and plasmapheresis are reserved as a means of rapidly helping the patient through a period of serious

myasthenia signs and symptoms.

A laboratory test to confirm the diagnosis of myasthenia gravis uses the patient’s sera as a

source of antibodies directed against the ACh receptor. Human cell lines, grown in the

laboratory and producing the ACh receptor, are used as a source of soluble receptor (the cells are

lysed and a solubilized membrane fraction, which contains the receptor, is obtained). The soluble

receptor is incubated with radioactively labeled α-bungarotoxin, which binds very specifically

and tightly to the ACh receptor. A sample of the patient’s sera is incubated with the bungarotoxin–

receptor complex, and the extent to which antibodies bind to the receptor complex is determined

as a measurement of reduced bungarotoxin binding to the receptor. A positive result indicates the

presence of anti-ACh receptor antibodies in the sera.

Ann R. Anorexia nervosa presents as a distorted visual self-image often associated with

compulsive exercise. Although Ann has been gaining weight, she is still relatively low on stored

fuels needed to sustain the metabolic requirements of exercise. Her prolonged starvation has resulted in

release of the steroid hormone cortisol and the polypeptide hormone glucagon, whereas levels of the

polypeptide hormone insulin have decreased. Cortisol activates transcription of genes for some of the

enzymes of gluconeogenesis (the synthesis of glucose from amino acids and other precursors; see Chapter

3). Glucagon binds to heptahelical receptors in liver and adipose tissue and, working through cAMP and

PKA, activates many enzymes involved in fasting fuel metabolism. Insulin, which is released when Ann

drinks her high-energy supplement, works through a specialized tyrosine kinase receptor to promote fuel

storage. Epinephrine, a catecholamine released when she exercises, promotes fuel mobilization.

Dennis V. In the emergency department, Dennis received intravenous rehydration therapy (normal

saline [0.9% NaCl]) and oral hydration therapy containing Na+, K+, and glucose or a digest of rice(which contains glucose and amino acids). Glucose is absorbed from the intestinal lumen via the sodiumdependent glucose cotransporters, which cotransport Na+ into the cells together with glucose. Many

amino acids are also absorbed by Na+-dependent cotransport. With the return of Na+ to the cytoplasm,

water efflux from the cell into the intestinal lumen decreases. Dennis quickly recovered from his bout of

cholera. Cholera is self-limiting, possibly because the bacteria remain in the intestine, where they are

washed out of the system by the diffuse watery diarrhea. Antibiotics (tetracycline or doxycycline) can

also be used, particularly in severe cases, to decrease the duration of the diarrhea and vibrio excretion.

Over the past 3 years, Percy V. has persevered through the death of his wife and the subsequent

calamities of his grandson Dennis V., including salicylate poisoning, suspected malathion poisoning, and

now cholera. Mr. V. has decided to send his grandson home for the remainder of the summer.

BIOCHEM ICAL COM M ENTS

Guanylyl Cyclase Receptors. Membrane-bound guanylyl cyclase receptors convert GTP to the

second messenger 3,5′ ′-cyclic GMP (cGMP), which is analogous to cAMP. These receptors will

directly synthesize cGMP in response to binding the appropriate ligand, unlike heptahelical receptors

which require G-protein signaling to adenylyl cyclase to produce cAMP. Like cAMP, cGMP is degraded

by a membrane-bound phosphodiesterase. Elevated cGMP activates protein kinase G, which then

phosphorylates target proteins to propagate the response. To date, seven such receptors have been

identified, although ligands for only four of the receptors have been positively confirmed.

A soluble form of guanylyl cyclase exists, located in the cytoplasm, and is a receptor for nitric oxide

(NO), a neurotransmitter/neurohormone. NO is a lipophilic gas that is able to diffuse into the cell. This

receptor thus is an exception to the rule that intracellular receptors are gene transcription factors. The

membrane-bound receptors will bind atrial natriuretic peptide, brain natriuretic peptide, and C-type

natriuretic peptide, as well as guanylin.

cGMP-elevating drugs have been used in humans to treat a variety of disorders such as angina

pectoris (glycerol trinitrate decomposes to NO, which activates a guanylyl cyclase), heart failure (using

nesiritide, which is synthetic β-natriuretic peptide, a ligand for activation of a guanylyl cyclase receptor),

and erectile dysfunction (through drugs that inhibit a cGMP phosphodiesterase [designated PDE5], such

as sildenafil). KEY CONCEPTS

In order to integrate cellular function with the needs of the organism, cells communicate with each

other via chemical messengers. Chemical messengers include neurotransmitters (for the nervous

system), hormones (for the endocrine system), cytokines (for the immune system), retinoids,

eicosanoids, and growth factors.

Chemical messengers transmit their signals by binding to receptors on target cells. When a

messenger binds to a receptor, a signal transduction pathway is activated which generates second

messengers within the cell.

Receptors can be either plasma membrane proteins or intracellular binding proteins. Intracellular receptors act primarily as transcription factors, which regulate gene expression inresponse to a signal being released.

Plasma membrane receptors fall into different classes, such as ion-channel receptors, tyrosine

kinase receptors, tyrosine kinase–associated receptors, serine–threonine kinase receptors, or Gprotein–coupled receptors (GPCRs), also known as serpentine receptors.

Ion-channel receptors respond to a stimulus by allowing ion flux across the membrane.

Tyrosine kinase and tyrosine kinase–associated receptors respond to a stimulus through

activation of a tyrosine kinase activity, which phosphorylates specific target proteins to elicit a

cellular response.

Serine–threonine kinase receptors respond to a stimulus that activates a serine–threonine kinase,

which then transmits signals through activation of Smad proteins, which are transcription

factors.

GPCRs respond to a stimulus by activating a guanine nucleotide-binding protein (G-protein),

which, in its activated GTP-binding state, activates a target protein. G-proteins contain intrinsic

GTPase activity, thereby limiting the time for which they are active.

Signal termination can occur via a variety of mechanisms such as destruction of the chemical

messenger; inactivation of second messages, such as loss of cAMP; or removal of covalent bonds

added as a result of the primary message (e.g., dephosphorylation). Diseases discussed in this chapter are summarized in Table 11.2. REVIEW QUESTIONS—CHAPTER 11

Questions 1 and 2 are based on the following patient.

1.A patient has severe weakness of a muscle group after repeatedly contracting that muscle group.

After rest, the muscle appears to function normally unless repeatedly contracted again. The antibody

causing this disease process would directly affect which one of the following? A. The number of ACh vesiclesB. Voltage-gated Ca2+ channels

C. Na+ and K+ gradients

D. ACh receptors in smooth muscle E. ACh receptors in skeletal muscle

2.In the patient described in the previous question, ACh and other similar neurotransmitters use which

one of the following modes of action to transmit their signal? A. Endocrine

B. Paracrine C. Autocrine D. Neuropeptide E. Cytokine

Use the following information to answer Questions 3 and 4. You do not need to know more about

parathyroid hormone or pseudohypoparathyroidism than the information given. Pseudohypoparathyroidism is a heritable disorder caused by target-organ unresponsiveness to

parathyroid hormone (a polypeptide hormone secreted by the parathyroid gland). One of the

mutations that causes this disease occurs in the gene encoding Gαs in certain cells.

3.The receptor for parathyroid hormone is most likely which one of the following? A. An intracellular transcription factor

B. A cytoplasmic guanylyl cyclase

C. A receptor that must be endocytosed in clathrin-coated pits to transmit its signal

D. A heptahelical receptor E. A tyrosine kinase receptor

4.This mutation most likely has which one of the following characteristics?

A.It is a gain-of-function mutation.

B.It decreases the GTPase activity of the Gαs subunit.

C.It decreases synthesis of cAMP in response to parathyroid hormone.

D.It decreases generation of IP3 in response to parathyroid hormone.

E.It decreases synthesis of PI-3,4,5-trisP in response to parathyroid hormone. 5. Techniques are available to allow one to introduce mutations in proteins at a selected amino acid

residue (site-directed mutagenesis). Which step of the signal transduction pathway would be blocked

if you created a tyrosine kinase receptor in which all of the tyrosine residues normally

phosphorylated on the receptor were converted to phenylalanine residues?

A.Grb2 binding to the receptor to propagate the response

B.Binding of the growth factor to the receptor

C.Induction of a conformational change in the receptor upon growth factor binding

D.Activation of the receptor’s intrinsic tyrosine kinase activity

E.Dimerization of the receptors

6. A patient has been diagnosed with a glucagonoma, a pancreatic tumor that

independently and

episodically secretes glucagon. Which one of the following would be expected in this patient?

A.Low serum glucose

B.Increased glycogenolysis in the liverC. Increased glycogenolysis in muscle tissue

D.Increased glycogenesis in the liver

E.Increased glycogenesis in muscle tissue

7. Curare has been given as a paralyzing agent in patients undergoing surgical procedures, and its mode

of action is best described by inhibiting the action of which one of the following?

A.Atropine

B.Muscarinic receptors

C.Nicotinic receptors

D.The formation of ACh

E.The breakdown of ACh

8.A patient with allergies is taking a drug that blocks the actions of leukotrienes. The leukotrienes are

derived from which one of the following molecules? A. Oleic acid

B. Linolenic acid C. Stearic acid

D. Arachidonic acid E. Palmitic acid

9.A pheochromocytoma is an adrenal tumor that episodically produces epinephrine and/or

norepinephrine. Tissues that respond to these adrenal hormones must express which one of the

following?

A. A tyrosine kinase receptor B. An intracellular receptor C. A ligand-gated receptor

D. The Smad transcription factor E. A heptahelical receptor

10.A male with chronic alcoholism and cirrhosis of the liver has low sexual desire, poor sexual

functioning, a need to shave only every 3 days, and normal-sized testicles. Which one of the

following best explains these symptoms?

A. Increased MEOS (microsomal ethanol oxidizing system) B. Decreased MEOS (microsomal ethanol oxidizing system) C. Normal thyroid hormone

D. Low serum albumin

E. Low plasma membrane receptors ANSWERS TO REVIEW QUESTIONS

1.The answer is E. This patient has myasthenia gravis caused by the production of an antibody

directed against ACh receptors in skeletal muscles (not smooth muscle), resulting in fewer

functional receptors but not affecting the number of ACh vesicles, Na+ and K+ gradients, or

voltage-gated Ca2+ channels.

2.The answer is B. Endocrine action is defined as a hormone secreted by a specific cell type withaction on specific target cells usually some distance away. Paracrine actions are hormones

secreted by a cell and binding to nearby cells. Autocrine action involves a messenger that acts on

the cell from which it was secreted. ACh activates only those ACh receptors located across the

synaptic cleft from the signaling nerve and not every cell that contains ACh receptors. ACh is a

nitrogen-containing small-molecule neurotransmitter or biogenic amine, not a neuropeptide.

Cytokines are messengers of the immune system.

3.The answer is D. Parathyroid hormone is a polypeptide hormone and thus must bind to a plasma