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Cell Communication
Signaling molecules &
Cell surface receptors
Cell Communication: An
Overview
 Cells
communicate with one another
through



Direct channels of communication
Specific contact between cells
Intercellular chemical messengers
Receptor animation
 Cell
surface receptors
Cell Communication
 To



survive, cells must
Communicate with their neighbors
Monitor environmental conditions
Respond appropriately
Cell Signaling
Apoptosis
Fig. 7-1, p. 140
Signals relayed between cells
Direct intercellular signaling
1.

Cell junctions allow signaling molecules to
pass from one cell to another
Direct Contact-dependent signaling
(Juxtacrine)
2.

Some molecules are bound to the surface of
cells and serve as signals to cell coming in
contact with them
Autocrine signaling
3.

Cells secrete signaling molecules that bind
to their own cell surface or neighboring cells
of the same type
8
Signals relayed between cells
Paracrine signaling
3.

Signal does not affect cell secreting the
signal but does influence cells in close
proximity (synaptic signaling)
Endocrine signaling
4.

Signals (hormones) travel long distances
and are usually longer lasting
9

Synaptic signaling is similar to paracrine
signaling but there is a special structure called
the synapse between the cell originating and the
cell receiving the signal. Synaptic signaling only
occurs between cells with the synapse; for
example between a neuron and the muscle that
is controlled by neural activity.
11
Cell Signaling
Signaling Molecules
 Small
molecules
 Peptides
 Proteins
 LIGANDS
Receptor affinity
 High

Low concentration of ligand; most receptors
are occupied
 Low

affinity
affinity
High concentration of ligand for most rectors
to be occupied
Receptor affinity
 Dissociation


constant Kd
Measures the affinity of the receptor-ligand
complex
The concentration of ligand at which half the
receptors are occupied
Example
 Erythroid
progenitor cell ~1000 surface
receptors for erythropoietin (Epo)
 Only 100 receptors need to bind Epo to
induce cell division
 Max cellular response less than Kd
Vasoconstriction occurs when epinephrine (adrenaline)
binds to the a-adrenergic receptor on vascular smooth
muscle cells. One approach to treating high blood
pressures is to administer competitive inhibitors that bind to
the a-adrenergic receptor. The Kd for binding of
epinephrine to this receptor is ~0.6 mM. Which of the
following compounds might be good candidate drugs for
high blood pressure? Kd for binding to the a-adrenergic
33%
receptor are shown
Compound A:
Kd = 1pM
2. Compound B:
Kd = 0.6 mM
3. Compound C:
Kd = 60 mM
.
33%
33%
1.
1
2
3
Intercellular Chemical
Messengers
 Controlling

Releases signal molecule that causes
response of target cells
 Target

cell processes signal in 3 steps:
Reception, transduction, response
 Signal

cell
transduction
Series of events from reception to response
3 stages of cell signaling
Receptor activation
1.

Signaling molecule binds to receptor
Signal transduction
2.

Activated receptor stimulates sequence of
changes- signal transduction pathway
Cellular response
3.

Several different responses
•
•
•
Alter activity of 1 or more enzymes
Alter structural protein function
Change gene expression– transcription factor
22
Signal Transduction
Fig. 7-2, p. 142
24
Amazing cells
 animation
Which of the following best describes a
signal transduction pathway?
Binding of a signal
molecule to a cell
protein
2. Catalysis mediated
by an enzyme
3. Series of changes in
a series of molecules
resulting in a
response
1.
33%
1
33%
2
33%
3
a. Reception by a cell-surface receptor
Polar (hydrophilic)
signal molecule
Activation
Receptor
embedded
in plasma
membrane
Target cell
Plasma
membrane
Polar signal molecules cannot pass through
the plasma membrane. In this case they
bind to a receptor on the surface.
Fig. 7-3a, p. 142
b. Reception by a receptor within cell
Nonpolar
(hydrophobic)
signal molecule
Activation
Receptor
within cell
Nonpolar signal molecules pass through
the plasma membrane and bind to their
receptors in the cell.
Fig. 7-3b, p. 142
Intracellular receptors
 Some
receptors are inside the cell
 Estrogen example


Passes through membrane and binds to
receptor in nucleus
Dimer of estrogen•receptor complexes binds
to DNA
• Transcription factors regulate transcription of
specific genes
29
30
Cell Communication Systems
with Surface Receptors
 Peptide

Primary extracellular signal molecules
recognized by surface receptors in animals
 Surface

hormones and neurotransmitters
receptors
Integral membrane glycoproteins
 Signaling


molecule
Bound by a surface receptor
Triggers response pathways within the cell
Surface Receptors
 Cell
communication systems based on
surface receptors have 3 components:
(1) Extracellular signal molecules
(2) Surface receptors that receive signals
(3) Internal response pathways triggered when
receptors bind a signal
Peptide Hormones
 Peptide

Small proteins
 Growth


hormones
factors
Special class of peptide hormones
Affect cell growth, division, differentiation
Neurotransmitters
 Neurotransmitters



include
Small peptides
Individual amino acids or their derivatives
Chemical substances
Surface Receptors
 Surface


Integral membrane proteins
Extend entirely through the plasma
membrane
 Binding

receptors
of a signal molecule
Induces molecular change in the receptor that
activates its cytoplasmic end
Ligand
 Signaling
molecule
 Binds noncovalently to receptor with high
degree of specificity
 Binding and release between receptor and
ligand relatively rapid
 Ligands alter receptor structureconformational change
 Once a ligand is released, the receptor is
no longer activated
36
Response of Surface Receptor
Fig. 7-4, p. 143
38
Cellular Response Pathways
 Cellular

Operate by activating protein kinases
 Protein

response pathways
kinases add phosphate groups
Stimulate or inhibit activities of target proteins,
producing cellular response
40
Cellular Response Pathways
 Protein


phosphatases
Reverse response
Remove phosphate groups from target
proteins
 Receptors

are removed by endocytosis
When signal transduction is finished
Phosphorylation
Fig. 7-5, p. 144
Amplification
 Each
step of a response pathway
catalyzed by an enzyme is amplified

Each enzyme activates hundreds or
thousands of proteins that enter next step in
pathway
 Amplification

Allows full cellular response when few signal
molecules bind to receptors
Amplification
Fig. 7-6, p. 145
45
Which of the following steps in an
intracellular signaling pathway amplifies the
signal?
1. Synthesis of a
25%
25%
25%
25%
secondary
messenger
2. Activation of a
protein kinase
3. Binding of ligand
to receptor
4. 1 & 2
1
2
3
4
In reactions mediated by protein kinases, what
does phosphorylation of successive proteins do
to drive the reaction?
1.
2.
3.
Make functional
ATP
Change a protein
from its inactive to
active form
Change a protein
from its active to
inactive form
33%
1
33%
2
33%
3
Which of the following is an
example of signal amplification?
1.
2.
3.
catalysis of many
cAMP molecules by
several simultaneously
binding signal
molecules
activation of 100
molecules by a single
signal binding event
activation of a specific
gene by a growth
factor
33%
1
33%
2
33%
3
Cell surface receptors
Enzyme-linked receptors
1.




Found in all living species
Extracellular domain binds signal
Causes intracellular domain to become
functional catalyst
Most are protein kinases
50
Receptor Tyrosine Kinases
 Receptor
tyrosine kinases bind signal
molecule


Protein kinase site becomes active
Adds phosphate groups to tyrosines in the
receptor itself, and to target proteins
 Phosphate
groups added to cytoplasmic
end of receptor are recognition sites for
proteins activated by binding to the
receptor
Protein Kinase Activity
Fig. 7-7, p. 146
Acetylcholine
 mimics
the electrical stimulation of the
vagus nerve. It is now known to be a
neurotransmitter at all autonomic ganglia,
at many autonomically innervated organs,
at the neuromuscular junction, and at
many synapses in the CNS.
What nerve!
 https://www.khanacademy.org/science/biol
ogy/human-biology/neuron-nervoussystem/v/anatomy-of-a-neuron
 http://www.biologymad.com/nervoussyste
m/nerveimpulses.htm
 Nerves are either “open” or “closed”
 The
neurotransmitter is broken down by a
specific enzyme in the synaptic cleft; for
example the
enzyme acetylcholinesterase breaks
down the neurotransmitteracetylcholine.
The breakdown products are absorbed by
the pre-synaptic neurone by endocytosis
and used to re-synthesise more
neurotransmitter, using energy from the
mitochondria. This stops the synapse
being permanently on.
Nerve agents
 Organochlorine
compounds work on
insects by opening what's known as the
sodium ion channel in the neurons or
nerve cells of insects, causing them to fire
spontaneously. The insect will go into
spasms and eventually die. DDT was the
earliest of these chlorinated hydrocarbons.
 Note: There are many other classes of
insecticides….this is just the one that
effects the “twitching”
Birth Control Pills “fool” the
Body
 The
lower levels of estrogen in birth
control pills suppress FSH (Follicle
Stimulating Hormone) and LH (luteinizing
hormone) "fooling" the pituitary gland into
thinking a woman is
pregnant. Ovulation will then not occur,
which prevents pregnancy.
 Go to next slide..
 The
progesterone in birth control pills
creates a thick cervical mucus, making it
difficult for sperm to reach theuterus. It
also impedes an egg from attaching itself
to the uterine lining (endometrium)
because of changes in the cellular
structure of the lining.
G-Protein–Coupled Receptors
G
proteins: Key molecular switches in
second-messenger pathways
 Two
major G-protein–coupled receptor
response pathways involve different
second messengers
G-Protein-Coupled Receptors
 G-protein-coupled
receptors activate
pathways

Binding of the extracellular signal molecule
(first messenger) activates a site on the
cytoplasmic end of the receptor
G-protein-coupled receptors
 Signals
binding to cell surface are first
messenger
 Many signal transduction pathways lead to
production of second messengers


Relay signals inside cells
Examples
• cAMP
• Ca2+
• Diacylglycerol and inositol triphosphate
63
G-Protein-Coupled Receptors
Fig. 7-8, p. 147
 Disruption
of G Protein signaling causes
several human diseases.
Vibrio cholerae (causes cholera) secretes
the cholera toxin which alters salt and fluid
in the intestine normally controlled by
hormones that activate Gs G-Protein to
increase cAMP.
 The
cholera toxin enzymatically changes
Gs so that it is unable to convert GTP to
GDP.
Gs can not then be inactivated and cAMP
levels remain high causing intestinal cell to
secrete salt and water.
Eventually dehydration can lead to death
(cholera).
Now what?
 How
does binding a signaling molecule
induce a cellular response?
68
G-protein-linkedreceptors
7-pass transmembrane
receptor
+ G protein
G protein = GTP binding
protein
G proteins are trimeric = 3
subunits
Inactive State
Receptor binds ligand
G-protein associates
with receptor
GTP is exchanged for
GDP - a subunit and
 subunit activated
The G-protein a-subunit
and  subunits are
activated
What next?
The active subunits
interact with target
proteins in the
membrane
What are some target proteins?
G-Protein Activation
 Activated
receptor turns on a G protein,
which acts as a molecular switch
G


protein
Active when bound to GTP
Inactive when bound to GDP
Active G Protein
 Active

G protein
Switches on the effector of the pathway
(enzyme that generates second messengers)
 Second


messengers
Small internal signal molecules
Activate the protein kinases of the pathway
Response Pathways
Fig. 7-9, p. 147
Second Messengers: cAMP
 1st
of two major pathways triggered by Gprotein-coupled receptors
 Effector
(adenylyl cyclase) generates
cAMP as second messenger
 cAMP
activates specific protein kinases
cAMP Receptor-Response
Pathways
Fig. 7-10, p. 148
cAMP
Fig. 7-11, p. 148
Adenylyl
cyclase
Phosphodiesterase
Pyrophosphate
ATP
cAMP
(second messenger)
AMP
Fig. 7-11, p. 148
81
 One
effect of cAMP is to activate protein
kinase A (PKA)
 Activated catalytic PKA subunits
phosphorylates specific cellular proteins
 When signaling molecules no longer
produced, eventually effects of PKA
reversed
82
83
cAMP has 2 advantages
1.
Signal amplification

2.
Binding of signal to single receptor can cause
the synthesis of many cAMP that activate
PKA, each PKA can phosphorylate many
proteins
Speed

In one experiment a substantial amount of
cAMP was made within 20 seconds after
addition of signal
84
Now what?
 How
does binding a signaling molecule
induce a cellular response?
Membrane-bound Enzymes
Second messengers
Adenylate cyclase
Adenylate Cyclase
a
cAMP
Adenylyl
cyclase
Always “on” so
cAMP is quickly
broken down
cAMP activates cAMP-dependent protein kinase
(A-kinase)
A-kinase phophorylates
serine/threonines of
selected proteins
Regulates the activity of the target
protein
Activated A-kinase
can modulate gene
regulation
Example of cell regulation by an
increase in cAMP levels
 Fight
or flight response- muscle cells
Fight or flight response
When an animal is frightened or
stressed the adrenal gland
releases epinephrine into the
bloodstream
Epinephrine example
 Fight-or-flight
hormone
 Different effects throughout body
 Stimulates heart muscle cells to beat
faster
 Caffeine inhibits phosphodiesterase


Enzyme removes cAMP once a signaling
molecule is no longer present
Inhibition causes cAMP to persist for longer
so heart beats faster
95
96
-adrenergic receptors
 Circulating
epinephrine binds
-adrenergic receptors on muscle and liver
cells
 Liberates glucose and fatty acids
 animation
A-kinase phosphoryates an
enzyme to break down
glycogen to release glucose
99
β- adrenergic receptors
 β-
adrenergic receptors are GPCR
 Different types are coupled to different G
proteins
 Gs (stimulatory) G proteins activate
adenylyl clyclase
 Gi (inhibitory) G proteins inhibit adenylyl
cyclase (α1 and α2)
Phophoprotein phosphatase (PP)
Pathway Controls
 cAMP
pathways are balanced by reactions
that eliminate second messengers


Stopped by protein phosphatases that
continually remove phosphate groups from
target proteins
Stopped by endocytosis of receptors and their
bound extracellular signals
103
Grb2SH2 adaptor protein
Sos Guanine nucleotide
exchange factor Ras-GEF
1. Receptor
binds ligand
2. Tyrosines
phosphorylated
4. Sos
exchanges
GTP for
GDP
3. Grb2/Sos bind
pY
Activated Ras recruits
Raf to the plasma
membrane Raf - protein kinase that
initiates the MAP kinase
cascade
Ras and Gα (trimeric G
proteins)
 Similar
structure and function and ubiquity
in eukaryotic cells suggest a single type of
GTPase originated early in evolution
 Gene encoding this ancestral protein
duplicated and evolved > 100 different
intracellular switch proteins
Active GTP
 Ras-GTP
active conformation
Ras-mitogen-activated protein
kinase (MAPK)
 Similar
to cAMP signaling cascade - both
provide pathways by which extracellular
signals can influence gene expression
Cascade of Protein Kinases
 Active
Ras activates Raf (ser/thr kinase)
 Raf activates MEK
 MEK activates MAPK
 MAPK activates other proteins
(transcription factors)
Gene Regulation: Ras
 Some
pathways in gene regulation link
certain receptor tyrosine kinases to a
specific G protein (Ras)
 When
the receptor binds a signal
molecule, it phosphorylates itself

Adapter proteins then bind, bridging to and
activating Ras
Activated Ras
 Activated
Ras turns on the MAP kinase
cascade
 Last
MAP kinase in cascade
phosphorylates target proteins in the
nucleus

Activates them to turn on specific genes
 Many
of these genes control cell division
Mutations
 Mutated
systems can turn on the
pathways permanently, contributing to
progression of some forms of cancer
The importance of Ras
 Early
1980’s, several human tumors
were found to contain a mutant of Ras
 Ras mutations are found in over 30% of
all human tumors
 Mutation in the Ras gene that lead to
tumor formation prevent the protein
from hydrolzying the bound GTP back
to GDP

Ras always “on”
The importance of Ras
 Ras
is a small G protein held to the
inner surface of the plasma membrane
by a lipid group that is embedded in the
inner leaflet of the bilayer
 Ras is a single subunit G protein
 Cycles between an active [GTP-bound]
form and an inactive [GDP-bound] form
 Activates a kinase cascade (MAP
Kinase)
Gene Regulation
Fig. 7-13, p. 151
Gene Activation:
Steroid Hormone Receptors
Fig. 7-14, p. 152
Cell Response
 Cell

response to a steroid hormone
Depends on whether it has an internal
receptor for the hormone
 Type

of response within the cell
Depends on the genes that are recognized
and turned on by an activated receptor
Cross-Talk
 Cell
signaling pathways communicate with
one another to integrate responses to
cellular signals
 May
result in a complex network of
interactions between cell communication
pathways
Cross-Talk
Fig. 7-15, p. 153
Core signaling
Pathways
Many target
proteins