Chapter 23

Signal Transduction Mechanisms:

II. Messengers and Receptors

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Chemical signals and cellular receptors

Most cells have some ability to sense and respond to specific

chemical signals.

Cells also produce signals by:

Displaying molecules on their surfaces that are recognized by

receptors on the surfaces of other cells; this kind of cell-to-cell
communication requires direct physical contact between cells.

Releasing chemical signals that are recognized by another cell,

either nearby or at a distant location.

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➢ Chemical signaling involves several key components

A variety of compounds can function as chemical messengers.

Signaling molecules are often classified based on the distance

between their site of production and the target tissues upon
which they act.

● Endocrine signals (from Greek words meaning “to secrete

into”); they are produced at great distances from their
target tissues and are carried by the circulatory system to
various sites in the body, such as hormones.

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● Paracrine signals (from the Greek para, which means “beside”)
are released locally, where they diffuse to act at short range
on nearby tissues, such as growth factors.

● Juxtacrine signals, when signals are passed at such short range

that they require physical contact between the sending and
receiving cells.

● Autocrine signals, local mediators act on the same cell that

produces them.

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 Receptors and ligands

Once a messenger reaches its target tissue, it binds to

receptors on the surface of the target cells, initiating the
signaling process.

A molecule coming from either a long or a short distance

functions as a ligand by binding to a receptor.

● A ligand often binds to a receptor embedded within the

plasma membrane of the cell receiving the signal.

● In other cases, such as steroid hormones, the ligand binds

to a receptor inside the cell.

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 In either case, the ligand is a “primary messenger”.

● The binding of ligand to receptor often results in the production

of additional molecules or ions within the cell receiving the signal.

● Such second messengers relay the signals from one location in

the cell, such as the plasma membrane, to the interior of the cell,
initiating a cascade of changes within the receiving cell.

✓ Signal transduction: the ability of a cell to translate a receptor-

ligand interaction to changes in its behavior or gene expression.

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 Messenger molecules can be chemically characterized as
amino acids or their derivatives, peptides, proteins, fatty
acids, lipids, nucleosides, or nucleotides.

● Many messengers are hydrophilic compounds whose function

lies entirely in their ability to bind to one or more specific
receptors on a target cell.

● Hydrophobic messengers act on receptors in the nucleus or

cytosol whose function is to regulate the transcription of
particular genes.

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 Receptor binding involves specific interactions between
ligands and their receptors.

● A messenger forms noncovalent chemical bonds with the

receptor protein; individual noncovalent bonds are generally
weak, several bonds must form to achieve strong binding.

● For a receptor to make numerous bond with its ligand, the

receptor must have a binding site (or binding pocket) that
fits the messenger molecule closely.

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● Within the ligand-binding site on the receptor, appropriate
amino acid side chains must be positioned so that they can
form chemical bonds with the messenger molecule.

● This combination of binding site shape and the strategic

positioning of amino acid side chains within the binding site
is what enables the receptor to distinguish its specific
ligand from thousands of other chemicals.

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 Some basic types of signaling pathways

There are many different types of signaling pathways, each

beginning with the binding of a ligand by its corresponding
receptor. These include:

● Ligand-gated ion channels, such as the acetylcholine receptor

● G protein-coupled receptors (GPCRs)
● Receptor kinases
● Nuclear receptors, such as steroid hormone receptors

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Cells can amplify signals once they are received

Exceedingly small quantities of a ligand are often sufficient to

elicit a response from a target cell, yet the responding cell reacts
in dramatic ways.

Often the strong response of the target cell results from a

signaling cascade with the responding cell.

At each step in the cascade, a signaling intermediate persists long

enough to stimulate the production of many molecules required
for the next step in the cascade, thereby multiplying the effects
of a single receptor-ligand interaction on the cell surface.

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 G protein-coupled receptors

➢ G protein-coupled receptors act via hydrolysis of GTP

The G protein-coupled receptors (GPCRs) are so named because

ligand binding causes a change in receptor conformation that
activates a particular G protein.

G protein: an abbreviation for guanine-nucleotide binding protein.

A portion of the activated G protein in turn binds to a target

protein, thereby altering the target’s activity.

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 The structure and regulation of GPCRs

G protein-coupled receptors all have a similar structure despite

differing significantly in their amino acid sequences.

The receptor forms seven transmembrane a helices connected

by alternating cytosolic or extracellular loops.

● The N-terminus of the protein is exposed to the extracellular

fluid, whereas the C-terminus resides in the cytosol.

● The extracellular portion of each GPCR has a unique messenger-

binding site, and the cytosolic loops allow the receptor to
interact with only certain types of G proteins.

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 GPCRs can be regulated in several ways.

● One of the most important is via phosphorylation of specific

amino acids in their cytosolic domain.

✓ When these amino acids are phosphorylated, the receptor

becomes desensitized.

✓ G protein-coupled receptor kinases (GRKs): specifically act on

activated receptors.

✓ Protein kinase A (PKA): itself activated by G protein-mediated

signaling; such inhibitory action is a example of negative
feedback during cell signaling.

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 The structure, activation, and inactivation of G proteins

G proteins act very much like molecular switches, whose “on” or

“off” state depends on whether the G protein is bound to GTP
or GDP.

There are two distinct classes of G proteins:

● The large heterotrimeric G proteins; contain three different

subunits, called Ga, Gb, and Gg.

● The small monomeric G proteins; Ras, Ras-like.

✓ Heterotrimeric G proteins mediate signal transduction through
G protein-coupled receptors.

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 G proteins have the same basic structure and mode of activation.

● Of the three subunits in the Gabg heterotrimer, Ga, the largest,

binds to a guanine nucleotide (GDP or GTP).

✓ When Ga binds to GTP, it detaches from the Gbg complex.

✓ The Gb and Gg subunits are permanently bound together.

● Some G proteins, such as Gs, act as stimulators of signal

transduction (s for “stimulatory”); others, such as Gi, act to
inhibit signal transduction (i for “inhibitory”).

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● Ga subunit catalyzes GTP hydrolysis; it remains active only
until it hydrolyzes its associated GTP to GDP, at which time
Ga reassociates with Gbg.

✓ Some Ga proteins are very inefficient at catalyzing GTP

hydrolysis; their efficiency is dramatically improved by
regulators of G protein signaling (RGS) proteins (GTPase
activating proteins, GAPs).

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➢ Cyclic AMP is a second messenger whose production is regulated
by some G proteins

Cyclic AMP (cAMP環腺苷酸) is formed from cytosolic ATP by the

enzyme adenylyl cyclase腺苷醯環化酶.

Adenylyl cyclase is anchored in the plasma membrane, with its

catalytic portion protruding into the cytosol.

● Normally, the enzyme is inactive until it binds to an activated Ga

subunit of a specific G protein, such as Gs.

● When GTP-Gsa binds to adenylyl cyclase, the enzyme becomes

active and converts ATP to cAMP.

● In contrast, Gia, inhibits adenylyl cyclase.

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抗利尿激素

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 cAMP levels would remain elevated in the cell if not for the
enzyme phosphodiesterase磷酸二酯酶, which degrades cAMP.

● cAMP appears to have one main intracellular target, the enzyme

protein kinase A (PKA).

✓ PKA phosphorylates a wide variety of cellular proteins by

transferring a phosphate from ATP to a serine or threonine
found within the target protein.

✓ cAMP regulates the activity of PKA by causing the detachment

of its two regulatory subunits from its two catalytic subunits.

✓ Once the catalytic subunits are free, PKA can catalyze the
phosphorylation of various proteins in the cell.

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➢ Many G proteins act through inositol trisphosphate and
diacylglycerol

Phospholipase C (磷脂酶C) cleaves phosphatidylinositol-4,5-

bisphosphate磷脂醯肌醇-4,5-雙磷酸(PIP2) into two molecules:
inositol trisphosphate肌醇三磷酸(IP3) and diacylglycerol二醯基
甘油(DAG).

Phosphatidylinositol-4,5-bisphosphate (PIP2) is a relatively

uncommon membrane phospholipid.

● IP3 and DAG are second messengers.

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凝血酶

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 IP3 is water soluble and quickly diffuses through the cytosol,
binding to a ligand-gated calcium channel known as the IP3
receptor in the endoplasmic reticulum.

● When IP3 binds, the channel opens, releasing calcium ions into the
cytosol; calcium then elicits the desired physiological response.

The DAG remains in the membrane, where it activates members of

the protein kinase C (PKC) family of enzymes.

● PKC can then phosphorylate specific serine and threonine groups

on a variety of target proteins, depending on the cell type.

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➢ The release of calcium ions is a key event in many signaling processes
Calcium ions (Ca2+) play an essential role in regulating a variety of
cellular functions.
The concentration of calcium is normally maintained at very low levels
in the cytosol due to the presence of calcium ATPases in the plasma
membrane and the endoplasmic reticulum.
● Calcium ATPases in the plasma membrane transport calcium out of
the cell; calcium ATPases in the ER sequester calcium ions in the
lumen of the ER.
In addition, some cells have sodium-calcium exchangers that further
reduce the cytosolic calcium concentration.

Mitochondria can transport calcium into the mitochondrial matrix.

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 Calcium binding activates many effector proteins

Calcium can bind directly to many different effector proteins,

altering their activity.

The response of a target cell to an increase in calcium concentration

depends on the particular calcium-binding proteins that are present
in the cell.

● This means that the same change in calcium concentration can

produce markedly different effects in two target cells if each
possesses different calcium-sensitive enzyme systems.

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 The calmodulin攜鈣素 molecule has been compared to a flexible
“arm” with a “hand” at each end.

● Two calcium ions bind at each of two “hand” regions, causing the
calmodulin to undergo a change in shape that forms the active
calcium-calmodulin complex.

● When a protein is present that contains a calmodulin-binding site,

the hands and arm bind to it by wrapping around the binding site.

● Calmodulin binding can influence the function of such a protein

dramatically.

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 An important feature of calmodulin is its affinity for calcium:

● Calmodulin binds to calcium when the cytosolic calcium

concentration increases to about 1.0 mM;

● Calmodulin releases calcium when cytosolic calcium levels decline

back to the resting level of 0.1 mM.

● Calmodulin is uniquely suited to operate within the typical range

of cytosolic calcium concentrations.

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➢ Nitric oxide一氧化氮 as the signal released by endothelial cells
that causes relaxation of the vascular smooth muscle

An important signaling molecule in the cardiovascular system is

nitric oxide (NO), a toxic, short-lived gas molecule produced by
the enzyme NO synthase, which converts the amino acid arginine
to NO and citrulline瓜氨酸.

Nitric oxide’s mode of action on blood vessels involves G proteins.

● Acetylcholine dilates blood vessels by causing their smooth

muscles to relax; NO as the signal released by endothelial cells
that causes relaxation of the vascular smooth muscle.

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 Binding of acetylcholine to the surface of vascular endothelial cells
results in release of NO:

● Acetylcholine binds to G protein-linked receptors that activate the

phosphoinositide signaling pathway, causing IP3 to be produced by
the endothelial cells.

● IP3 causes the release of calcium from the endoplasmic reticulum.

● The calcium ions bind to calmodulin, forming a complex that
stimulates NO synthase to produce nitric oxide.

● Nitric oxide is a gas that readily diffuses through plasma

membranes, allowing it to pass from the endothelial cell into the
adjacent smooth muscle cells.

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● Once inside the smooth muscle cell, NO activates the enzyme
guanylyl cyclase鳥苷酸環化酶, which catalyzes the formation of
cyclic GMP (cGMP); cGMP can act as a second messenger.

● The increase in cGMP concentration activates a protein known as

protein kinase G, which induces muscle relaxation by catalyzing
the phosphorylation of the appropriate muscle proteins.

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➢ The bg subunits of G proteins can also engage in signaling

For example, G protein receptor kinases can be activated by the bg

subunit of a dissociated G protein, providing a feedback mechanism
on G protein signals.

One well-studied example of Gbg signaling involves the muscarinic

acetylcholine receptor乙醯膽鹼蕈毒接受器.

When acetylcholine binds the muscarinic acetylcholine receptor, the

bg subunit of its associated G protein (Gi) acts on potassium channels
in the plasma membrane, causing them to open.

● When acetylcholine is no longer present, the a and bg subunits re-

associate, causing the potassium channels to close again.
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 Another example of Gbg signaling involves signaling in the budding
yeast, Saccharomyces cerevisiae.

Yeast use G protein-mediated signaling during mating and to sense

changes in osmolarity, availability of nutrients, and other
environmental factors.

● Interestingly, the activated bg subunits in this initiate a series of

phosphorylation events that lead to activation of a type of kinase
known as MAP kinase.

● MAP kinases are key proteins in another type of signaling pathway

in higher eukaryotes, the receptor tyrosine kinase pathway.

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Protein kinase-associated receptors

Protein kinase-associated receptors not only function as

receptors, but also are themselves protein kinases.

When these receptor kinases bind to the appropriate ligand,

their kinase activity is stimulated, and they transmit signals
through a cascade of phosphorylation events within the cell.

Receptor kinases generally fall into two major categories:

Those that phosphorylate a tyrosine residue (tyrosine kinases);

Those that phosphorylate serine or threonine residues

(serine/threonine kinases).

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➢ Growth factors often bind protein kinase-associated receptors

Growth factors present within the serum血清.

Plasma血漿 is whole blood, including unreacted platelets but without

the red and white blood cells.

Serum is the clear fluid remaining after blood has clotted.

● During clotting, platelets secrete growth factors into the blood that
stimulate the proliferation of cells called fibroblasts纖維母細胞, which
form the new connective tissue that makes up a scar.

● After clotting, the resulting serum is full of platelet-derived growth

factor (PDGF).

● Plasma does not contain this factor, because the clotting reaction
has not taken place.
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➢ Receptor tyrosine kinases aggregate and undergo
autophosphorylation

Many receptor tyrosine kinases (RTKs) trigger a chain of signal

transduction events inside the cell that ultimately lead to cell
proliferation or cell specialization.

Examples of RTKs include the insulin receptor, the nerve growth

factor receptor, and the epidermal growth factor (EGF) receptor.

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 The structure of receptor tyrosine kinases

These receptors often consist of a single polypeptide chain

with only one transmembrane segment.

● The extracellular portion of the receptor contains the ligand-

binding domain.

● The other end of the peptide protrudes through the plasma

membrane into the cytosol.

✓ On the cytosolic side, a portion of the receptor forms the

tyrosine kinase.

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 The cytosolic portion of the receptor contains tyrosine residues
that are themselves targets for phosphorylation.

● The tyrosine kinase is frequently an integral part of the receptor

protein.

● In some cases, however, the receptor and the tyrosine kinase are
two separate proteins, and the tyrosine kinase is then referred to
as a nonreceptor tyrosine kinase.

✓ Nonreceptor tyrosine kinase can bind to the receptor, and be

activated when the receptor binds its ligand, so the net effect is
quite similar to the activation of a typical receptor tyrosine kinase.

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 The activation of receptor tyrosine kinases

Signal transduction is initiated when a ligand binds, causing the

receptor tyrosine kinases to aggregate.

● Once the receptors cluster, the tyrosine kinase associated with

each receptor phosphorylates the tyrosines of neighboring
receptors.

● Because the receptors phosphorylate other receptors of the

same type, this process is referred to as autophosphorylation.

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➢ Receptor tyrosine kinases initiate a signal transduction cascade
involving Ras and MAP kinase

Once autophosphorylation of tyrosine residues on the cytosolic

portion of the receptor occurs in response to ligand binding, the
receptor can recruit a number of cytosolic proteins.

Each of these proteins binds to a region of the receptor that

contains a stretch of amino acids that includes a phosphotyrosine
and a few neighboring amino acids.

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 The portion of a protein that recognizes one of these phosphorylated
tyrosines is called an SH2 domain.

● The term SH2, for Src homology (domain) 2, was originally used
because proteins with SH2 domains have sequences of amino acids
that are strikingly similar to a portion of the Src protein.

Recruitment of different SH2 domain-containing proteins activates

different signal transduction pathways.

● As a result, RTKs can activate several different signal transduction

pathways at the same time.

● These include the inositol-phospholipid-calcium second messenger

pathway and the Ras pathway, which ultimately activates the
expression of genes involved in growth or development.
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 Ras comprises a single subunit; Ras and other small monomeric
G proteins are important signaling molecules.

Like other G proteins, Ras can be bound to either GDP or GTP,

but it is active only when bound to GTP.

● In the absence of receptor stimulation, Ras is normally in the

GDP-bound state.

● For Ras to become active, it must release GDP and acquire a

molecule of GTP; for this to take place, Ras needs the help of
another type of protein called a guanine-nucleotide exchange
factor (GEF).

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● The GEF that activates Ras is Sos (a genetic mutation in fruit flies
called son of sevenless that results in the failure of cells in the
compound eye to develop properly).

✓ For Sos to become active, it must bind indirectly to the receptor

tyrosine kinase through another protein, called GRB2, which
contains an SH2 domain.

✓ To activate Ras, the receptor becomes tyrosine phosphorylated, and

GRB2 and Sos form a complex that binds to the receptor, activating
Sos.

✓ Sos then stimulates Ras to release GDP and acquire GTP, which
converts Ras to its active state.

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 Once Ras is active, it triggers a series of phosphorylation reactions.

● The first protein in this cascade is a protein kinase called Raf.

● Activated Raf in turn phosphorylates serine and threonine residues
in a protein kinase known as MEK.

● MEK can then phosphorylate threonines and tyrosine residues in a

class of proteins known as mitogen-activated protein kinases, or
MAP kinases (MAPKs).

● One function of MAPKs is to phosphorylate transcription factors

(such as Jun, Ets) that regulate the expression of genes whose
protein products are needed for cells to grow and divide.

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 Once Ras is in its active state, it must be inactivated by hydrolysis
of the GTP bound to it to avoid continued stimulation of the Ras
pathway.
● GTP hydrolysis is facilitated by a GTPase activating protein (GAP).
● GAP can accelerate inactivation of Ras 100-fold.

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➢ Receptor tyrosine kinases activate a variety of other signaling
pathways

Receptor tyrosine kinases, like G protein-linked receptors, can

also activate phospholipase C.

Phospholipase Cg is activated by receptor tyrosine kinases; it

contains an SH2 domain and must bind to the receptor.

● Once it binds to the receptor, phospholipase Cg is phosphorylated

by the RTK and becomes active.

Phospholipase Cb is activated by the G protein-coupled receptors.

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 In addition, receptor tyrosine kinases can activate other
enzymes, such as phosphatidylinositol 3-kinase (PI 3-kinase),
which phosphorylates the plasma membrane phospholipid
phosphatidylinositol.

This enzyme is important in regulating cell proliferation and

cell movement.

● The roles of this kinase are diverse and complex.

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➢ Other growth factors transduce their signals via receptor
serine/threonine kinases

Another major class of protein kinase-associated receptors

phosphorylate serine and threonine residues.

One major class of serine/threonine kinase receptors comprises

a family of proteins that bind members of the transforming
growth factor b (TGFb)轉形生長因子 family of growth factors.

This growth factor family regulates a wide range of cellular

functions in both embryos and adult animals, including cell
proliferation, programmed cell death, the specialization of cells,
and key events in embryonic development.

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 The first step in TGFb signaling is the binding of growth factor
by the transmembrane receptor.

● In general, TGFb family members bind to two types of receptors

within the receiving cell: the type I and type II receptors.

● When ligand is bound, the type II receptor phosphorylates the

type I receptor.

● The type I receptor then initiates a signal transduction cascade

within the cell, phosphorylating a class of proteins known as
Smads.

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● There are three types of Smads:
✓ Those that are phosphorylated by a complex of anchoring proteins and
activated receptors are known as receptor-regulated, or R-Smads.

✓ Another Smad, Smad4, forms a multiprotein complex with

phosphorylated R-Smads.

# When Smad4 molecules bind R-Smads, the entire complex can move
into the nucleus, where it can associate with other cofactors and
DNA-binding proteins to regulate gene expression.

✓ Still other Smads act at various points in TGFb signaling to inhibit the
pathway; one type can bind to and inhibit receptors, whereas another
can bind and inhibit Smad4.
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● Smad signals are terminated when the R-Smad is degraded or
the R-Smad moves back into the cytosol, where it can be reused
when the cell receives another signal.

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➢ Scaffolding complexes can facilitate cell signaling

In many cases, cells need to regulate precisely where signaling occurs

so that they can mount a response in a very specific spot.

To do so, signaling components are sometimes assembled into large

multiprotein complexes, which make such cascading reactions級聯效應
more efficient and confine the cellular signals to a small area in the
cell.

A well-studied example of a signaling scaffold involves the mating

pathway of the budding yeast, Saccharomyces cerevisiae.

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 In budding yeast, mating factor signaling is mediated through
the activated Gbg subunit of a G protien.

Gbg recruits a large scaffolding protein, known as Ste5, to the

plasma membrane.

● Ste5 increases the efficiency of signal transduction through

the mating pathway by assembling the kinases involved into a
large complex.

● In this case, a specific phosphorylation cascade results in the

phosphorylation of MAP kinase (MAPK).

● MAPK in turn phosphorylates other proteins, leading to changes

in gene expression that are important for mating.
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➢ Different signaling pathways are integrated through crosstalk

In addition to localizing and organizing signaling complexes via

scaffolds, a cell must integrate its response to the multiple signals to
which it is exposed. How can it do so ?

Sometimes a single receptor can activate multiple pathways.

In still other cases, different ligands bind their corresponding

receptors at the cell surface, activating specific signaling pathways
within the cell; activated components from one pathway can then
affect components in another pathway.

In other cases, different pathways converge onto the same molecules,

such as second messengers.

Such interactions are collectively known as signaling crosstalk.

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 Hormonal signaling and other long-range signals

➢ Hormones can be classified by their chemical properties

To coordinate signals involving many different tissues and organs,

plants and animals use secreted chemical signals called hormones.

Endocrine hormones travel by means of the circulatory system

from the cells where they are released to other cells where they
regulate one or more specific functions.

● As they circulate in the bloodstream, hormone molecules come

into contact with receptors in tissues throughout the body.

● A tissue that is specifically affected by a particular hormone is

called a target tissue for that hormone.
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● The heart and the liver are
target tissues for epinephrine;
the liver and skeletal muscles
are targets for insulin.

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Chemically, the endocrine hormones fall into four categories:

Amino acid derivatives; epinephrine derived from tyrosine.

Peptides; antidiuretic hormone (vasopressin血管加壓素).

Proteins; insulin.

Lipid-like hormones such as the steroids; the steroid hormones

are derivatives of cholesterol that are synthesized either in the
gonads性腺 (the sex hormones) or in the adrenal cortex (the
corticosteroids).

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➢ The endocrine system controls multiple signaling pathways to
regulate glucose levels

The adrenergic hormones epinephrine and norepinephrine

Epinephrine is also called adrenaline; the two words are Greek

and Latin derivation, respectively, and mean “above, or near,
the kidney”, referring to the location in the body of the
adrenal glands, which synthesize this hormone.

The overall strategy of adrenergic hormone actions is to put

many of the normal bodily functions on hold and to deliver vital
resources to the heart and skeletal muscles instead, as well as
to produce a heightened state of alertness.

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 Adrenergic hormones bind to a family of G protein-coupled receptors
known as adrenergic receptors腎上腺素受器.

Adrenergic receptors can be broadly classified into a- and b-

adrenergic receptors.

● The a-adrenergic receptors bind both epinephrine and norepinephrine.

✓ These receptors are located on the smooth muscles that regulate
blood flow to visceral organs.

● The b-adrenergic receptors bind epinephrine much better than

norepinephrine.

✓ These receptors are found on smooth muscles associated with

arterioles that feed the heart, smooth muscles of the bronchioles細支
氣管 in the lungs, and skeletal muscles.
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 The a- and b-adrenergic receptors stimulate different signal
transduction pathways because they are linked to different
G proteins.

● The a-adrenergic receptors activate Gq proteins, whereas the

b-adrenergic receptors activate Gs.

✓ Activation of Gs stimulates the cAMP signal transduction

pathway, leading to relaxation of certain smooth muscles.

✓ Activation of Gq stimulates phospholipase C, leading to the

production of IP3 and DAG, which in turn elevates intracellular
calcium levels.

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 Adrenergic hormones and control of glycogen degradation

One action of the adrenergic hormones is to stimulate the

breakdown of glycogen to provide muscle cells with an adequate
supply of glucose.

● The breakdown of glycogen is facilitated by the enzyme glycogen

phosphorylase肝糖磷解酶, which catalyzes a reaction in which the
glycosidic linkage between two glucose subunits undergoes attack
by inorganic phosphate.

● This results in release of a molecule of glucose-1-phosphate.

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● When an epinephrine molecule binds to a b-adrenergic receptor, the
receptor activates a neighboring Gs protein, and the Gs protein in
turn stimulates adenylyl cyclase, which generates cAMP from ATP.

✓ The resulting transient increase in the concentration of cAMP in

the cytosol activates protein kinase A.

✓ PKA then activates another cascade of events that begins with the
phosphorylation of the enzyme phosphorylase kinase磷解酶激酶.

✓ This leads to the conversion of glycogen phosphorylase from

phosphorylase b, the less active form, to phosphorylase a, the more
active form, and thus to an increased rate of glycogen breakdown.

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● cAMP also stimulates the inactivation of the enzyme system
responsible for glycogen synthesis.

✓ PKA also phosphorylates the enzyme glycogen synthase;

phosphorylation inactivates it.

● Thus the overall effect of cAMP involves both an increase in

glycogen breakdown and a decrease in its synthesis.

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Insulin signaling and PI 3-kinase

During periods of normal activity, two hormones produced by

specialized cells in the pancreas known as islets of Langerhans,
regulate blood glucose levels.

The glucagon昇糖激素 acts via the same Gs protein activated by

epinephrine, and so it acts to increase blood glucose by the
breakdown of glycogen when the level of glucose in the blood is
too low.

Insulin reduces the blood glucose levels by stimulating uptake of

glucose into muscle and adipose cells脂肪細胞 and by stimulating
glycogen synthesis.

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Insulin has both very rapid and longer-lasting effects on a
variety of cells.

In muscle and adipose cells, insulin causes uptake of glucose

within a few minutes and does not require the synthesis of
new proteins.

Long-term effects of insulin, such as production of enzymes

involved in glycogen synthesis, require higher levels of insulin
sustained over many hours.

To exert its effects, insulin binds to receptor tyrosine kinases.

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 The insulin receptor has two a subunits and two b subunits.

● When insulin binds the receptor, b subunits of the receptor

phosphorylate a protein called insulin receptor substrate 1 (IRS-
1).

● Phosphorylated IRS-1 can stimulate two different pathways:

✓ First, IRS-1 can recruit GRB2, activating the Ras pathway.

✓ Second, IRS-1 can bind an enzyme known as phosphatidylinositol

3-kinase (PI 3-kinase, or PI3K); PI 3-kinase then catalyzes the
addition of a phosphate group to the plasma membrane lipid PIP2,
which converts PIP2 into PIP3.

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● PIP3 in turn recruits protein kinases to the inner surface of the
plasma membrane, which ultimately leads to phosphorylation and
activation of a protein kinase called Akt (protein kinase B).

● Activation of Akt has two important consequences:

✓ First, it leads to movement of a glucose transporter protein
(GLUT4) from vesicles in the cytosol to the plasma membrane,
allowing glucose uptake.

✓ Second, Akt can phosphorylate glycogen synthase kinase-3

(GSK-3), reducing its activity; this leads to an increase in the
amount of the unphosphorylated, more active form of glycogen
synthase.

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➢ Steroid hormones bind receptors in the cytosol and carry them
into the nucleus

Not all hormone receptors act at the cell surface; steroid

hormones bind to receptors that act primarily in the nucleus
rather than at the cell surface.

These steroid receptor proteins mediate the actions of steroid

hormones such as progesterone, estrogen, testosterone, and
glucocorticoids.

Steroid hormones are hydrophobic molecules synthesized by

cells in endocrine tissues.

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 The steroid hormones are released into the bloodstream,
where they bind to blood plasma proteins and travel
throughout the body.

● After entering a target cell, a steroid hormone binds to its

corresponding receptor, triggering a series of events that
ultimately activates, or in a few cases inhibits, the
transcription of a specific set of genes.

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