Key points:

• Homeostasis denotes the stable condition of the internal

environment that results from the operation of compensatory
homeostatic control systems.
• In a negative feedback control system, a change in the
variable being regulated brings about responses that tend to
push the variable in the direction opposite to the original
change. Negative feedback minimizes changes from the set
point of the system, leading to stability.
• Homeostatic control systems minimize changes in the
internal environment but cannot maintain complete constancy.

• The components of a homeostatic reflex arc are the

receptor, afferent pathway, integrating center, efferent
pathway, and effector. The pathways may be neural or
hormonal.
 Housekeeping:

Weekly Online Assignment # 1: You can find this

assignment on our Canvas site at on the Topic 1 -
Organization of the Body and Homeostasis page.

This assignment is due on Friday, January 24th at 12pm

(EST).
Biology 336 - Human Physiology

Lecture 3 – Tuesday, January 21st, 2025

Review of Cell Signaling I

Reading: Stanfield, 6th Ed. Chapter 5

Pages 124-128, 134-145
Model 2A from Thursday’s
POGIL activity
focus of
today :

O
 Outline: Cell Signaling
1) How cells communicate: signal transduction and 2nd
messengers.
2) Small signaling or hydrophobic molecules enter target cells
↓
and bind intracellular receptors.
can cross plasma

i) Nitric-oxide as a signal membrane

ii) Steroid hormonal cues

3) Most signaling molecules bind cell-surface receptors.
i) G-protein linked receptors
ii) Ion-channel linked receptors
iii) Enzyme linked receptors
 Learning objectives
At the end of this lecture, you will be able to:

1. Describe the general mechanisms of cell signaling, including use of

signal transduction, second messengers, and signal amplification
within the cell.

2. Compare the two broad classes of signaling molecules in the body.

3. Describe the role of the small signaling molecule, Nitric oxide (NO),
in triggering smooth muscle relaxation in a blood-vessel wall.

4. Explain the mechanism of action of steroid hormones upon target

cells using Cortisol as an example.
 Learning objectives
At the end of this lecture, you will be able to:

5. List the series of events required to activate and inactivate the G-

protein of a G-protein linked receptor.

6. Compare the activation of the enzymes (i) Adenylyl cyclase and (ii)
Phospholipase C by the GTP-bound α subunit of an activated G-
protein.
1. Signal transduction is any process by which a cell
converts one kind of signal or stimulus into another.
Ÿ Signal transduction involves a
sequence of reactions carried out by
hydrophilic
enzymes and linked through second
messengers (see next slide).

Ÿ Such processes take place in as

little time as a millisecond or as long
as a few seconds.
Ÿ In many transduction processes, an
increasing number of enzymes and
other molecules become engaged in
the events that proceed from the initial
stimulus. The chain of steps is referred
to as a "signaling cascade.”
 Second messengers are molecules that relay signals
received at receptors on the cell surface
Ÿ Second messengers relay
signals — such as the arrival
of protein hormones, growth
factors, etc. — to target
molecules in the cytosol
and/or nucleus.

Ÿ Additionally, second
messengers serve to
amplify the strength of the
signal. I bind receptor

i
= make 100s of cAMP
cannot be
amplified response
proteins/enzymes
=>

Ÿ >
Examples of second
-
messengers include cyclic nucleotides
(e.g., cyclic AMP and cyclic GMP) and Calcium ions (Ca2+).
 Consider the following:

2. Which characteristic do second messenger molecules

share between them that also distinguish them from the
rest of the molecules in a signal transduction pathway?

A. they are all ions

B. they are all cyclic nucleotides
O
C. they are not proteins
D. they are all small peptides
E. they are all activated through G proteins

To respond to poll, please go to: www.pollev.com/patrickcafferty

2. Extracellular signal molecules fall into one of
two classes
1. The smaller class of signals
consists of molecules that are small
or hydrophobic enough to slip easily
through the plasma membrane and
activate intracellular enzymes or
bind to intracellular receptors to
regulate gene expression. (for e.g. –
Nitric Oxide and Cortisol)

2. The largest class of signals

consists of molecules too hydrophilic
to cross the plasma membrane of
the target cell. They rely on cell
surface receptors to relay messages
into the cell. (for e.g. – Insulin)
2. Extracellular signal molecules fall into one of
two classes
1. The smaller class of signals
consists of molecules that are small
or hydrophobic enough to slip easily
through the plasma membrane and
activate intracellular enzymes or
bind to intracellular receptors to
regulate gene expression. (for e.g. –
Nitric Oxide and Cortisol)

2. The largest class of signals

consists of molecules too hydrophilic
to cross the plasma membrane of
the target cell. They rely on cell
surface receptors to relay messages
into the cell. (for e.g. – Insulin)
 Consider the following:

3. When a chemical messenger (also called a "ligand")

reaches a target cell, it binds to a receptor. In general, a
hydrophobic ligand binds to a(n) __________, whereas a
hydrophilic ligand binds to a(n) __________.

O
A. intracellular receptor; transmembrane receptor
B. transmembrane receptor; intracellular receptor
C. intracellular receptor; intracellular receptor
D. transmembrane receptor; transmembrane receptor
E. none of the above answers are correct.

To respond to poll, please go to: www.pollev.com/patrickcafferty

 Key points:
• Cells in multicellular organisms communicate through a large
variety of extracellular chemical signals. Cells are
stimulated by an extracellular signal molecule when that
molecule binds to and activates a receptor protein. Each
receptor protein recognizes a particular signal molecule.

• Receptor proteins act as transducers, converting signals from

one physical form to another.

• Signaling molecules that are small or hydrophobic enough

can slip easily through the plasma membranes of target cells.
3. Endothelial cells are the specialized, flattened
epithelial cells that line every blood vessel.

↓ NO cnitric Oxide)
 Signaling
Nitric Oxide (NO) is a dissolved gas that diffuses out of
endothelial cells & enters neighboring smooth muscle cells.

molecule
(
really
(not
and
messeng

Nitric oxide binds to the enzyme Guanylyl

cyclase, stimulating formation of cGMP.
 The gas nitric oxide (NO) causes the relaxation of
smooth muscles of the blood vessels.
Ÿ Acetylcholine causes increased Ca2+ levels in
the endothelial cells, which causes the activation of
NO synthase, the enzyme that makes NO.
Ÿ NO diffuses rapidly from the
endothelial cells to the nearby
smooth muscle cells.

me
Ÿ In the smooth muscle cells, NO
activates the enzyme guanylyl cyclase,
which stimulates the formation of cGMP.
 Viagra promotes smooth
muscle relaxation in the
vasculature

eit PD
Viagra enhances the effects of
NO by inhibiting the enzyme
griagra
PRIT
Phosphodiesterase (PDE)
that normally breaks down
cGMP, prolonging the NO
signal, thus prolonging penile
erection.
4. Individuals possessing a mutation in the gene encoding
the enzyme, Nitric Oxide Synthase (NOS) overproduce the
signaling molecule, Nitric Oxide (NO) resulting in low blood
pressure. On a cellular level, which one of the following would
be helpful in reducing the harmful effects of this NOS gene
mutation?
A. Increasing the amount of cyclic guanosine monophospate
(cGMP) in smooth muscle cells.
S
B. Increasing the activity of the enzyme phosphodiesterase in
smooth muscle cells.
C. Increasing the Acetylcholine signal sent to endothelial cells.
D. Inhibiting activation of the Acetylcholine receptors in
endothelial cells.
E. Decreasing the activity of the enzyme phosphodiesterase in
endothelial cells.
To respond to poll, please go to: www.pollev.com/patrickcafferty
4. Hydrophobic steroid hormones cross the
plasma membrane of the target cell
• Steroid hormones all pass
through the plasma
membrane of the target
cell.

• In the cell, the hormones bind

to, and activate receptors found
in the cytoplasm or nucleus.
Low surface , ex .
EGFR)

• Upon activation, the hormone

receptors are capable of
regulating gene transcription.
 Key points:
• Nitric oxide (NO) is an
example of a small signaling
molecule released from the
endothelial cells of blood
vessels that can cross directly
into neighboring smooth muscle
cells to trigger relaxation.

• Hydrophobic signal molecules such as the steroid

hormones—including cortisol, estradiol, and
testosterone—and the thyroid hormones such as
thyroxine all pass through the plasma membrane of
target cells.
Extracellular signal molecules fall into one of
two classes
1. The smaller class of signals
consists of molecules that are small
or hydrophobic enough to slip easily
through the plasma membrane and
activate intracellular enzymes or
bind to intracellular receptors to
regulate gene expression. (for e.g. –
Nitric Oxide and Cortisol)

2. The largest class of signals

consists of molecules too hydrophilic
to cross the plasma membrane of
the target cell. They rely on cell
surface receptors to relay messages
into the cell. (for e.g. – Insulin)
Hydrophilic signaling molecules bind cell-surface
receptors.

i) G-protein linked receptors ii) Ion-channel linked receptors

iii) Enzyme linked receptors

Hydrophilic signaling molecules bind cell-surface
receptors.

i) G-protein linked receptors ii) Ion-channel linked receptors

iii) Enzyme linked receptors

 5. The G-protein linked receptor family is the largest
family of cell-surface receptors.
• Several types of G-proteins exist—each binds a specific type
of receptor and set of downstream targets. All G-proteins
have a similar structure and operate in a similar way.
• The trimeric G-
proteins are composed
of a, b, and g subunits
and are tethered to the
membrane inside the
g a cell.
b
• Inactive G-proteins
are bound by GDP at
the a subunit.
↓
active GDP-GTP
:
The G-protein linked receptor family is the largest family
of cell-surface receptors.
• A hydrophilic signal binds to the extracellular
side of the receptor and changes the shape of
the receptor on the cytoplasmic side..

This exposes a binding Ÿ G protein activation

site for the G protein. triggers a detachment of
the a and the b and g
subunits from the
receptor and each other
g a
b
to roam the plasma
membrane.

-wholemolecule
.
• Binding of the G protein to late
receptor triggers the exchange of new nory
GDP with GTP by the a subunit, not GDP phisp
activating the G protein. .
to GTP
 The effector protein may catalyze many
reactions, amplifying the signal.
• The activated a and bg G-protein subunits can both
interact directly with target proteins in the plasma
membrane that can relay the signal to other destinations.

• The a and bg complex

proteins remain dissociated
and active until the a
subunit hydrolyses the
bound GTP to GDP.
g a
b
• GTP hydrolysis causes the
a subunit to reassociate with
the bg subunits and the
signal is shut off.
 5. If a G protein were unable to release its bound nucleotide but
could hydrolyze it, signal transduction would:
O
A. not move beyond this point.
B. be continuous beyond this point.
C. be unaffected.
D. be constantly switching on and off.
E. be unpredictable.

6. If a G protein could release its bound nucleotide but was not

able to hydrolyze it, signal transduction would:
A. not move beyond this point.
O
B. be continuous beyond this point.
C. be unaffected.
D. be constantly switching on and off.
E. be unpredictable.

To respond to poll, please go to: www.pollev.com/patrickcafferty

 Key points:
• There are three main classes of cell-surface receptors: (1)
G-protein-linked receptors; (2) ion-channel-linked
receptors; and (3) enzyme-linked receptors.

• G protein-linked receptors activate a class of trimeric GTP-

binding proteins called G proteins; these act as molecular
switches, transmitting the signal onward for a short period
and then switching themselves off by hydrolyzing their
bound GTP to GDP.
Biology 336 - Human Physiology

Lecture 4 – Thursday, January 23rd, 2025

Cell signaling (continued) and endocrine system

features and major classes of hormones

Reading: Reading: Stanfield, 6th Ed. Chapter 5

Pages 126-134
Model 2A from last week’s
POGIL activity
 Outline: Cell Signaling
1) How cells communicate: signal transduction and 2nd
messengers.
2) Small and hydrophobic signaling molecules enter target
cells and bind intracellular receptors.
to

i) Nitric-oxide as a signal small membrane

Zcross
-

cells .
ii) Steroid hormonal cues -

hydrophobic target
3) Most signaling molecules bind cell-surface receptors.
i) G-protein linked receptors >
- Activate: exchange GDP - GTP

ii) Ion-channel linked receptors

iii) Enzyme linked receptors
 Learning objectives
At the end of this lecture, you will be able to:
Review of cell signaling (continued):

1. Compare the activation of the enzymes (i) Adenylyl cyclase

and (ii) Phospholipase C by the GTP-bound α subunit of an
activated G-protein.

2. Describe the function of ion channel-linked receptors.

3. Describe the response of the Epidermal Growth Factor

Receptor (EGFR) to EGF binding, including activation of the RAS
small G-protein and the MAP kinase cascade.
 Learning objectives
At the end of this lecture, you will be able to:

Endocrinology:

4. Interpret the results of Arnold Berthold’s 1849 experiment

using roosters, the first formal experiment in endocrinology.

5. Describe the general features of the endocrine system.

1. Several types of trimeric G-proteins exist—each
binds a specific type of receptor and set of
downstream targets.

Don't memorize. But look at this

 In this lecture, we will focus on:

(i) The G-protein GS that activates the enzyme,

adenylyl cyclase (also called adenylate cyclase).

(ii) The G-protein GQ that activates the enzyme,

phospholipase C.
 i) GTP-bound GS activates Adenylyl cyclase, an
enzyme that catalyzes cyclic AMP (cAMP) formation.

• The cAMP 2nd messenger activates

the enzyme Protein Kinase A, involved
p
-

in a wide-range of biological processes

including long-term memory. eps
-
phosphat
<

• cAMP is quickly degraded

by Phosphodiesterase. Fast

·"
cAMP degradation is
necessary to maintain
sensitivity of the cell to
extracellular signal
molecules—a lack of cAMP
degradation results in a
failure of response to further
extracellular signals.
One of the many physiological actions of caffeine
is to act as a Phosphodiesterase (PDE) inhibitor.

viagra/coffee

Ÿ This action is similar to that of Viagra.

A rise in intracellular cAMP can activate gene
transcription.
Ÿ In the cytosol, cAMP
activates PKA which then
moves into the nucleus and
phosphorylates specific gene
regulatory proteins.

Ÿ Once phosphorylated, these

proteins stimulate the
transcription of a whole set of
target genes. PKA can also
phosphorylate proteins in the
cytosol.
 1. Cholera toxin can affect cells by inhibiting the
ability of the G protein α subunit to hydrolyze GTP to
GDP.

On a cellular level, which one of the following would be helpful

in reducing the harmful effect of cholera toxin?

A. Increasing the amount of intracellular cAMP.

①
B. Inhibiting the activity of adenylyl cyclase in the cell.
C. Adding ligand for the G-protein coupled receptor in this
pathway.
D. Increasing the amount of protein kinase A activity in the
cell.
E. Inhibiting the activities of the β and γ G-protein subunits.
To respond to poll, please go to: www.pollev.com/patrickcafferty
A rise in intracellular cAMP can activate gene
transcription.
Ÿ In the cytosol, cAMP
activates PKA which then
moves into the nucleus and
phosphorylates specific gene
regulatory proteins.

Ÿ Once phosphorylated, these

proteins stimulate the
transcription of a whole set of
target genes. PKA can also
phosphorylate proteins in the
cytosol.
 ii) GTP-bound GQ activates Phospholipase C
Ÿ Phospholipids can be hydrolyzed into components that act as
second messengers.

Phosphatidyl inositol-
bisphosphate (PIP2) is
hydrolyzed into inositol
triphosphate (IP3) and
diacylglycerol (DAG).
 GTP-bound GQ activates Phospholipase C
Ÿ The two parts each become second messengers, with IP3
moving into the cytoplasm and DAG remaining in the membrane.
. • DAG together with Calcium, activates
the enzyme Protein kinase C.

• IP3 binds to and opens

Calcium channels in the ER.
2. How does Diacylglycerol (DAG) function in a G-protein
coupled receptor pathway? Diacylglycerol (DAG):

A. activates phospholipase C.
B. activates protein kinase G.
C. on its own, recruits and activates Protein Kinase C (PKC).
⑧
D. together with calcium, activates Protein Kinase C (PKC).
E. binds to and opens calcium channels in the plasma
membrane, allowing extracellular calcium to enter the
cytosol.

To respond to poll, please go to: www.pollev.com/patrickcafferty

 Key points:
• Several types of trimeric G-proteins exist—each binds a
specific type of receptor and set of downstream targets. All G-
proteins have a similar structure and operate in a similar way.

• The activated, GTP-bound α-subunit of the G-protein, GS

activates the enzyme adenylyl cyclase that catalyzes
formation of the second messenger, cAMP.

• The activated, GTP-bound α-subunit of the G-protein, GQ

activates the enzyme phospholipase C that catalyzes
formation of the second messengers, DAG and IP3.
2. Ion channel-linked receptors convert hydrophilic
chemical signals into electrical signals.
Act
ligand • Ion channel-linked receptors can open to let

gated
certain ions (for e.g. Na+, K+, Ca2+, or Cl-) in or out
of a cell and are responsible for rapid-transmission
of signals across synapses in the nervous system.

Ÿ Ion channels transduce a

chemical signal, in the form of a
pulse of neurotransmitter (a
hydrophilic chemical signal)
delivered to the outside of the
target cell, directly into an
electrical signal, in the form of a
change in voltage across the
plasma membrane of the target
cell.
 3. Response of the Epidermal Growth Factor
gar
Inactive n
aReceptor (EGFR) to EGF binding
1. Epidermal Growth
Factor (EGF) interacts
with the external
domain of EGFR,

=
triggering
dimerization.

2. Dimerization
stimulates enzymatic
activity of the &Mass Activating
intracellular catalytic
-
Protein

domain, resulting in
- Adds O to the
-

trans- other tail.

autophosphorylation
of EGFR.
Response of the Epidermal Growth Factor Receptor
(EGFR) to EGF binding
3. Downstream cytoplasmic proteins
become activated by binding to
EGFR phospho-tyrosine residues.

4. The downstream proteins

build a bridge between the
receptor tyrosine kinase (RTK)
and the Ras protein, which is
subsequently activated.
3. The primary amino acid sequence of the Epidermal Growth
Factor Receptor (EGFR) contains an invariant lysine amino acid
essential for kinase activity. Substitution of this essential lysine by
any other amino acid blocks the capacity of the receptor to
phosphorylate targets. What stage of receptor activation is
disrupted by substitution of the invariant lysine with another amino
acid?

When this lysine is replaced by another amino acid:

A. EGFR is unable to activate an associated trimeric G-protein.

B. the ligand Epidermal Growth Factor (EGF) is unable to bind to
EGFR.
C. docking sites for EGFR target proteins are not generated inside
the cell.
D. EGFR becomes constitutively activated, that is, EGFR is always
on.
E. enzymatically inactive EGFR monomers are unable to dimerize.
Ras is a monomeric G-protein that belongs to the
“small GTPase” family.
• Ras is a small protein bound by a lipid tail to the cytoplasmic
surface of the plasma membrane.

Ÿ The Ras protein is a member of the small, single-subunit GTP-

binding proteins and is active when bound with GTP, inactive
when bound with GDP.
 Activated Ras triggers a MAP kinase
phosphorylation cascade
• Ras activates a phosphorylation cascade in which a series
of protein kinases phosphorylate and activate one another in
sequence.

• This sequence of events is

called a MAP-kinase cascade
after the Mitogen-Activated
Protein, the final kinase in the
cascade.
Ÿ At the end of the signal
cascade, MAP-kinase
phosphorylates regulatory
proteins on serine and
threonine residues (amino
acids).
4. A mutation in the gene encoding the enzyme Mitogen
Activated Protein Kinase Kinase (MAPKK) produces a
constitutively activated form of MAPKK, leading to tumor
formation.

On a cellular level, which of the following would be helpful in

reducing the harmful effect of the MAPKK gene mutation?
A) Increasing the activity of Mitogen Activated Protein Kinase
(MAPK) in the cell.

8B) Inhibiting the activity of Mitogen Activated Protein Kinase

(MAPK) in the cell.
C) Adding ligand for the Epidermal Growth Factor Receptor
(EGFR).
D) Inhibiting activity of the monomeric G-protein, RAS.
E) Inhibiting the activity of Mitogen Activated Protein Kinase
Kinase Kinase (MAPKKK).
 Ÿ 30% of human
cancers involve
mutations of the Ras
gene.

• Ras was first identified in

human cancer cells, in which a
mutation in the Ras gene
produced a hyper-active form
of Ras.
Ÿ Mutant Ras proteins are
unable to dissociate GTP, so
they are stuck in the ON or
active conformation, constantly
stimulating the cell to divide.
5. Mutant Ras proteins, that are found in many cancer
cells, can't hydrolyze their bound GTP to GDP, and therefore:

A. can't turn themselves on.

B. can't turn themselves off.
C. can't be degraded.
D. they are able to activate Mitogen-Activated Protein Kinase
(MAPK) directly.

To respond to poll, please go to: www.pollev.com/patrickcafferty

 Key points:
• Many enzyme-linked receptors have intracellular enzymatic
domains. The receptor tyrosine kinases (RTKs) are the largest
class of enzyme-linked receptors. RTKs phosphorylate
tyrosine amino acids of target proteins.

• Activated RTKs cause

the assembly of an
intracellular signaling
complex on the
intracellular tail of the
receptor. Part of this
complex serves to
activate the monomeric
G-protein, Ras.
 Key points:
• Ras activates a protein kinase cascade that relays
information from the plasma membrane to the nucleus.
4. Castration and re-implantation or transplantation of
testes in roosters revealed the existence of a chemical
signaling molecule in the blood.
6. Which of the following statements about Arnold Berthold’s 1849
experiment on roosters is FALSE?

A. Berthold hypothesized the testes release a chemical signal that

causes male roosters to act aggressively toward one another.
B. Castrated young male roosters were known to be docile and to
not grow large combs and wattles.
C. Castrated birds with testes re-implanted into their own
abdominal cavities, as well as control castrated birds, acted
aggressively and grew large wattles and combs.
D. Testes implanted into birds’ abdominal cavities did not form new
neural connections with the body, but they did establish new
blood vessels.
E. Berthold had discovered testosterone although the chemical
was not isolated and named until years later.

To respond to poll, please go to: www.pollev.com/patrickcafferty

 5. The endocrine system involves hormone
secretion into the interstitial fluid.
• The two major communication
systems of the body are:
1) The nervous system – is
specialized for rapid communication
accomplished through electrical
impulses in neurons.
2) The endocrine system – is
composed of glands and hormone-
secreting cells located in various
organs (such as the heart, kidneys,
liver, and stomach). Signals sent by
the endocrine system have longer
delays but last for greater lengths of
time than nervous signals.
This is not a complete list—see Table 6-1
(pg 157-158) for more detail.
A single endocrine gland may secrete multiple
hormones.

Pancreas • For example, the pancreas

secretes a number of
hormones, including Insulin
which lowers blood glucose
levels, Glucagon that
increases blood glucose levels,
and Somatostatin that inhibits
secretion of pancreatic
hormones.
A single endocrine gland may secrete multiple
hormones.

Pancreas

• In general, single cell types in

glands secrete only one
hormone, so multiple-hormone
secretion reflects the presence
of different types of endocrine
cells in the same gland.
 Chemical messengers secreted by an endocrine-
gland cell may also be secreted by other cell types.

Ÿ For example, norepinephrine is used as both a

neurotransmitter in the nervous system and is an endocrine
hormone secreted by the adrenal medulla.
 7. Which of the following statements regarding the
endocrine system is true? The endocrine system:

A. releases hormones into the bloodstream for

circulation throughout the body.
B. produces signals that have much longer delays and
last for much greater lengths of time than nervous
system signals.
C. is composed of endocrine glands and hormone-
producing cells located throughout the body.
D. all of the above statements regarding the endocrine
system are true.

To respond to poll, please go to: www.pollev.com/patrickcafferty

Copyright © 2010 Pearson Education, Inc.
 Key points:
• Endocrine hormones are chemical messengers that enter
the blood, that carries them from their site of secretion to the
cells upon which they act.

• Endocrine hormones functionally link various organs

together, for example, the hormone ACTH (adrenocortiotropic
hormone) links the anterior pituitary to the adrenal glands.

• Signals sent by the endocrine system have longer delays

but last for greater lengths of time than nervous system
signals.