The Cellular Internet

Cell-to-cell communication is essential for

multicellular organisms
Biologists have discovered some universal
mechanisms of cellular regulation

Exchange of
mating factors

a factor

Receptor

Yeast cell, a factor

mating type a

Yeast cell,
mating type a

Mating
a

New a/a cell

a/a

Local and Long-Distance Signaling

Cells in a multicellular organisms communicate by
chemical messengers
Animal and plant cells have cell junctions that
directly connect the cytoplasm of adjacent cells
In local signaling, animal cells may communicate
by direct contact
In many other cases, animal cells communicate
using local regulators, messenger molecules that
travel only short distances
In long-distance signaling, plants and animals
use chemicals called hormones

Plasma membranes

Gap junctions
between animal cells
Cell junctions

Cell-cell recognition

Plasmodesmata
between plant cells

Local signaling

Long-distance signaling

Target cell

Secreting
cell

Local regulator
diffuses through
extracellular fluid
Paracrine signaling

Electrical signal
along nerve cell
triggers release of
neurotransmitter

Endocrine cell

Neurotransmitter
diffuses across
synapse

Secretory
vesicle

Target cell
is stimulated

Blood
vessel

Hormone travels
in bloodstream
to target cells

Target
cell

Synaptic signaling

Hormonal signaling

The Three Stages of Cell Signaling: A Preview

Earl W. Sutherland discovered how the hormone
epinephrine acts on cells

Sutherland suggested that cells receiving signals

went through 3 processes:
Reception
Transduction
Response

EXTRACELLULAR
FLUID

CYTOPLASM
Plasma membrane

Reception

Transduction

Response

Receptor
Activation
of cellular
response
Relay molecules in a signal transduction
pathway
Signal
molecule

Reception: A signal molecule binds to a receptor

protein, causing it to change shape
The binding between a signal molecule (ligand)
and receptor is highly specific

A conformational change in a receptor is often the

initial transduction of the signal
Most signal receptors are plasma membrane
proteins

Intracellular Receptors
Some receptor proteins are intracellular, found in
the cytosol or nucleus of target cells
Small or hydrophobic chemical messengers can
readily cross the membrane and activate
receptors

Examples of hydrophobic messengers are the

steroid and thyroid hormones of animals
An activated hormone-receptor complex can act
as a transcription factor, turning on specific
genes

Hormone
(testosterone)

EXTRACELLULAR
FLUID

Plasma
membrane

Receptor
protein

Hormonereceptor
complex

The steroid
hormone testosterone
passes through the
plasma membrane.

Testosterone binds
to a receptor protein
in the cytoplasm,
activating it.

The hormonereceptor complex

enters the nucleus
and binds to specific
genes.
DNA
The bound protein
stimulates the
transcription of
the gene into mRNA.

mRNA

NUCLEUS

New protein
The mRNA is
translated into a
specific protein.

CYTOPLASM

Receptors in the Plasma Membrane

Most water-soluble signal molecules bind to
specific sites on receptor proteins in the plasma
membrane
There are three main types of membrane
receptors:
G-protein-linked receptors
Receptor tyrosine kinases
Ion channel receptors

 A G-protein-linked receptor is a plasma

membrane receptor that works with the help of a G
protein
The G-protein acts as an on/off switch: If GDP is
bound to the G protein, the G protein is
inactive

Signal-binding site

Segment that
interacts with
G proteins

G-protein-linked receptor

 Receptor tyrosine kinases are membrane

receptors that attach phosphates to tyrosines
A receptor tyrosine kinase can trigger multiple
signal transduction pathways at once
A kinase, alternatively known as a
phosphotransferase, is a type of enzyme that
transfers phosphate groups from high-energy
donor molecules, such as ATP, to specific
substrates. The process is referred to as
phosphorylation.

Signal
molecule

Signal-binding site

a Helix in the
membrane

Signal
molecule

Tyrosines

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Receptor tyrosine
kinase proteins
(inactive monomers)

CYTOPLASM

Dimer

Activated relay
proteins

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

ATP

Activated tyrosinekinase regions

(unphosphorylated
dimer)

6 ADP

P Tyr
P Tyr
P Tyr

Tyr

P
P
Tyr P

Tyr

Fully activated receptor

tyrosine-kinase
(phosphorylated
dimer)

P Tyr
P Tyr
P Tyr

P
Tyr P
Tyr P
Tyr

Inactive
relay proteins

Cellular
response 1
Cellular
response 2

 An ion channel receptor acts as a gate when the

receptor changes shape
When a signal molecule binds as a ligand to the
receptor, the gate allows specific ions, such as
Na+ or Ca2+, through a channel in the receptor

Signal
molecule
(ligand)

Gate
closed

Ligand-gated
ion channel receptor

Ions

Plasma
membrane

Gate open

Cellular
response

Gate closed

Transduction: Cascades of molecular

interactions relay signals from receptors to
target molecules in the cell
Transduction usually involves multiple steps
Multistep pathways can amplify a signal: A few
molecules can produce a large cellular
response
Multistep pathways provide more opportunities for
coordination and regulation

Signal Transduction Pathways

The molecules that relay a signal from receptor to
response are mostly proteins
Like falling dominoes, the receptor activates
another protein, which activates another, and so
on, until the protein producing the response is
activated
At each step, the signal is transduced into a
different form, usually a conformational change

Protein Phosphorylation and Dephosphorylation

In many pathways, the signal is transmitted by a
cascade of protein phosphorylations

Phosphatase enzymes remove the phosphates

This phosphorylation (kinases) and
dephosphorylation (phosphatases) system acts
as a molecular switch, turning activities on and off

Signal molecule

Receptor
Activated relay
molecule
Inactive
protein kinase
1

Active
protein
kinase
1
Inactive
protein kinase
2

ATP
ADP

Pi

Active
protein
kinase
2

PP

Inactive
protein kinase
3

ATP

ADP

Pi

Active
protein
kinase
3

PP

Inactive
protein

ATP

ADP

Pi

PP

Active
protein

Cellular
response

Small Molecules and Ions as Second Messengers

Second messengers are small, nonprotein,
water-soluble molecules or ions

The extracellular signal molecule that binds to the

membrane is a pathways first messenger
Second messengers can readily spread
throughout cells by diffusion
Second messengers participate in pathways
initiated by G-protein-linked receptors and
receptor tyrosine kinases

Cyclic AMP
Cyclic AMP (cAMP) is one of the most widely
used second messengers

Adenylyl cyclase, an enzyme in the plasma

membrane, converts ATP to cAMP in response
to an extracellular signal

Phosphodiesterase

Adenylyl cyclase

Pyrophosphate
P

ATP

H2O

Pi

Cyclic AMP

AMP

 Many signal molecules trigger formation of cAMP

Other components of cAMP pathways are G
proteins, G-protein-linked receptors, and protein
kinases
cAMP usually activates protein kinase A, which
phosphorylates various other proteins
Further regulation of cell metabolism is provided
by G-protein systems that inhibit adenylyl cyclase

First messenger
(signal molecule
such as epinephrine)

Adenylyl
cyclase

G protein

G-protein-linked
receptor

GTP

ATP
cAMP

Second
messenger

Protein
kinase A

Cellular responses

Calcium ions and Inositol Triphosphate (IP3)

Calcium ions (Ca2+) act as a second messenger
in many pathways

Calcium is an important second messenger

because cells can regulate its concentration

EXTRACELLULAR
FLUID

Plasma
membrane
Ca2+
pump

ATP

Mitochondrion

Nucleus

CYTOSOL

Ca2+
pump
Endoplasmic
reticulum (ER)
ATP

Key

Ca2+
pump

High [Ca2+]

Low [Ca2+]

 A signal relayed by a signal transduction pathway

may trigger an increase in calcium in the cytosol

Pathways leading to the release of calcium involve

inositol triphosphate (IP3) and diacylglycerol
(DAG) as second messengers

EXTRACELLULAR Signal molecule

FLUID
(first messenger)
G protein
DAG
GTP

G-protein-linked
receptor

Phospholipase C

PIP2
IP3 (second
messenger)

IP3-gated
calcium channel

Endoplasmic
Ca2+
reticulum (ER)

CYTOSOL

Ca2+
(second
messenger)

Various
proteins
activated

Cellular
responses

Cytoplasmic and Nuclear Responses

Ultimately, a signal transduction pathway leads to
regulation of one or more cellular activities

The response may occur in the cytoplasm or may

involve action in the nucleus
Many pathways regulate the activity of enzymes

Reception
Binding of epinephrine to G-protein-linked receptor (1 molecule)

Transduction
Inactive G protein
Active G protein (102 molecules)

Inactive adenylyl cyclase

Active adenylyl cyclase (102)

ATP
Cyclic AMP (104)

Inactive protein kinase A

Active protein kinase A (104)

Inactive phosphorylase kinase

Active phosphorylase kinase (105)

Inactive glycogen phosphorylase

Active glycogen phosphorylase (106)
Response
Glycogen
Glucose-1-phosphate
(108 molecules)

 Many other signaling pathways regulate the

synthesis of enzymes or other proteins, usually by
turning genes on or off in the nucleus
The final activated molecule may function as a
transcription factor

Growth factor

Reception

Receptor

Phosphorylation
cascade
Transduction

CYTOPLASM

Inactive
transcription Active
transcription
factor
factor

Response

DNA
Gene
NUCLEUS

mRNA

Fine-Tuning of the Response

Multistep pathways have two important benefits:
Amplifying the signal (and thus the
response)
Contributing to the specificity of the
response

Signal Amplification
Enzyme cascades amplify the cells response
At each step, the number of activated products
is much greater than in the preceding step

The Specificity of Cell Signaling

Different kinds of cells have different collections of
proteins

These differences in proteins give each kind of cell

specificity in detecting and responding to signals
The response of a cell to a signal depends on the
cells particular collection of proteins
Pathway branching and cross-talk further help
the cell coordinate incoming signals

Signal
molecule

Receptor

Relay
molecules

Response 1
Cell A. Pathway leads
to a single response

Response 2

Response 3

Cell B. Pathway branches,

leading to two responses

Activation
or inhibition

Response 4

Cell C. Cross-talk occurs

between two pathways

Response 5

Cell D. Different receptor

leads to a different response

Signaling Efficiency: Scaffolding Proteins and

Signaling Complexes
Scaffolding proteins are large relay proteins
to which other relay proteins are attached
Scaffolding proteins can increase the signal
transduction efficiency

Signal
molecule

Plasma
membrane

Receptor
Three
different
protein
kinases
Scaffolding
protein

Termination of the Signal

Inactivation mechanisms are an essential aspect
of cell signaling

When signal molecules leave the receptor, the

receptor reverts to its inactive state

Animations and Videos

Biomembranes II: Membrane Dynamics and
Communication
Bozeman - Cell Communication
Bozeman - Evolutionary Significance of Cell
Communication

Cell Junctions
Tight Junctions

Desmosomes
Gap Junctions

Animations and Videos

Bozeman - Signal Transduction
Second Messengers (cAMP and Ca+2 Pathways)

Chemical Synapse 1
Chemical Synapse 2

Voltage-Gated Channels and the Action Potential

Signal Transduction Pathway
Signaling by Secreted Molecules
Signal Transduction

Animations and Videos

2nd Messenger
Signal Amplification 1

Signal Amplification 2
Hormonal Communication
Mechanism of Steroid Hormone Action
Mechanism of Thyroxine Action
Action of Epinephrine on a Liver Cell
Action of Glucocorticoid Hormone

Animations and Videos

Intracellular Receptor Model
Mechanism of Action of Lipid-Soluble Messengers

Mechanism of Thyroxine Action

Mechanism of Steroid Hormone Action

Lipid Soluble Hormone

Chapter Quiz Questions 1

Chapter Quiz Questions - 2

Which of the following gives a correct and

broadest description of signal transduction
pathways?
binding of a signal molecule to a cell protein

catalysis mediated by an enzyme

sequence of changes in a series of molecules
resulting in a response
binding of a ligand on one side of a membrane
that results in a change on the other side

the cells detection of a chemical or mechanical

stimulus

Which of the following gives a correct and

broadest description of signal transduction
pathways?
binding of a signal molecule to a cell protein

catalysis mediated by an enzyme

sequence of changes in a series of molecules
resulting in a response
binding of a ligand on one side of a membrane
that results in a change on the other side

the cells detection of a chemical or mechanical

stimulus

Matching:
Match each receptor type (13) to a distinctive
feature of it (AE):
1) channel receptors
2) G protein-coupled receptors
3) receptor tyrosine kinases

phosphorylation

activation of a G protein

ion influx into the cell

dephosphorylation

ATP synthesis

Matching:
Match each receptor type (13) to a distinctive
feature of it (AE):
1) channel receptors
2) G protein-coupled receptors
3) receptor tyrosine kinases

phosphorylation

activation of a G protein

ion influx into the cell

dephosphorylation

ATP synthesis

A steroid hormone is bound by an intracellular

receptor. When it does, the resulting complex is
most likely to do which of the following?
open channels in the membrane for other
substances to enter
open channels in the nuclear envelope for
cytoplasmic molecules to enter
mediate the transfer of phosphate groups to/from
ATP

act as a transcription factor in the nucleus

make water-soluble molecules able to diffuse
across membranes

A steroid hormone is bound by an intracellular

receptor. When it does, the resulting complex is
most likely to do which of the following?
open channels in the membrane for other
substances to enter
open channels in the nuclear envelope for
cytoplasmic molecules to enter

mediate the transfer of phosphate groups to/from

ATP
act as a transcription factor in the nucleus
make water-soluble molecules able to diffuse
across membranes

Weak ionic bonds formed between the negative

phosphate functional group and partially or fully
positive amino acids of proteins in a kinase
cascade do which of the following?
make functional ATP
distort a protein from one functional state
to another
activate phosphatases to remove the phosphate
group
alter the permeability of the cells membranes
produce an increase in the cells store of
inorganic phosphates

Weak ionic bonds formed between the negative

phosphate functional group and partially or fully
positive amino acids of proteins in a kinase
cascade do which of the following?
make functional ATP
distort a protein from one functional state
to another
activate phosphatases to remove the phosphate
group
alter the permeability of the cells membranes
produce an increase in the cells store of
inorganic phosphates

Which of the following is the best example of

amplification of signal detection?
production of many molecules by many signal
molecules

activation of 100 molecules by a single signal

binding event
activation of a specific gene by a transcription
factor
conversion of the signal into many other types of
molecules
activation of a receptor by a hormone

Which of the following is the best example of

amplification of signal detection?
production of many molecules by many signal
molecules

activation of 100 molecules by a single signal

binding event
activation of a specific gene by a transcription
factor
conversion of the signal into many other types of
molecules
activation of a receptor by a hormone

Which choice CORRECTLY describes what

happens during the transduction part of a signal
transduction response pathway?
Some fraction of the original signal is converted into
something else and passed through the cell.
Changes in protein activities and in other items
in the cell are induced by an activated receptor.

The original signal is amplified as it is passed through the

cell.
Energy from the signal is used to power the
changes needed in the cell for a response.
Some phenotypic feature of the cell is altered.

Which choice CORRECTLY describes what

happens during the transduction part of a signal
transduction response pathway?
Some fraction of the original signal is converted into
something else and passed through the cell.
Changes in protein activities and in other items in the
cell are induced by an activated receptor.

The original signal is amplified as it is passed through the

cell.
Energy from the signal is used to power the
changes needed in the cell for a response.
Some phenotypic feature of the cell is altered.

Which best describes what a plasma membrane-spanning

receptor (see figure) actually does upon reception of a
signal?
The receptor binds an extracellular signal molecule and
passes it into the cell.

Activated receptors directly produce a response to the

signal.
It uses the energy from the signal to
power its transduction.
Binding of the signal molecule alters
the receptors other binding sites
and activities.
It amplifies the signal, increasing its
influence in the cell.

Which best describes what a plasma membrane-spanning

receptor (see figure) actually does upon reception of a
signal?
The receptor binds an extracellular signal molecule and
passes it into the cell.

Activated receptors directly produce a response to the

signal.
It uses the energy from the signal to
power its transduction.
Binding of the signal molecule alters
the receptors other binding sites
and activities.
It amplifies the signal, increasing its
influence in the cell.

Of the following events, which might typically occur

THIRD in the course of a cells receiving and responding
to a signal?
An enzyme cascade occurs, increasing the number of
activated proteins.

A signal molecule is bound by a transmembrane tyrosine

kinase receptor protein.
The receptor protein complex phosphorylates other
proteins.
A reconfigured protein binds
to DNA, altering gene
expression.
Tyrosine kinase receptor
subunits dimerize.

Of the following events, which might typically occur

THIRD in the course of a cells receiving and responding
to a signal?
An enzyme cascade occurs, increasing the number of
activated proteins.

A signal molecule is bound by a transmembrane tyrosine

kinase receptor protein.
The receptor protein complex phosphorylates other
proteins.
A reconfigured protein binds
to DNA, altering gene
expression.
Tyrosine kinase receptor
subunits dimerize.

Which of the following statements CORRECTLY describes the

use of ligand-gated ion channel receptors?
Ligand binding is irreversible, resulting in a permanent
change in this ion channels activity.
The binding site of this type of receptor is most often
in the middle of the membrane.
Once activated, this receptor will cause G proteins to
bind with GTP.
Once the ligand is bound, the ion channel activity can
alter the local membrane potential and cytosolic
concentration of the ion.
The ligand involved is often a phosphate
group that is covalently added to the
cytosolic side of this ion channel.

Which of the following statements CORRECTLY describes the

use of ligand-gated ion channel receptors?
Ligand binding is irreversible, resulting in a permanent
change in this ion channels activity.
The binding site of this type of receptor is most often
in the middle of the membrane.
Once activated, this receptor will cause G proteins to
bind with GTP.
Once the ligand is bound, the ion channel activity can
alter the local membrane potential and cytosolic
concentration of the ion.
The ligand involved is often a phosphate
group that is covalently added to the
cytosolic side of this ion channel.

Sutherland found evidence for the presence of a G proteincoupled receptor for epinephrine in muscle cells. For this
receptor to function normally, it must have at least how
many binding sites, and what must be bound?
one: G protein

two; epinephrine and G protein

two: epinephrine and GTP
one: extracellular epinephrine
three: epinephrine, G protein, and
ATP

Sutherland found evidence for the presence of a G proteincoupled receptor for epinephrine in muscle cells. For this
receptor to function normally, it must have at least how
many binding sites, and what must be bound?
a) one: G protein

b) two; epinephrine and G protein

c) two: epinephrine and GTP
d) one: extracellular epinephrine

e) three: epinephrine, G protein, and

ATP

Which is NOT an option that is sometimes used by

cells in some type of information transduction?
The binding abilities of several proteins are
altered.

The original signal is amplified many times over.

A cellular compartment has a change in the
concentration of a specific item.
Proteins are covalently modified.
A membrane potential gradient is altered.

Which is NOT an option that is sometimes used by

cells in some type of information transduction?
The binding abilities of several proteins are
altered.

The original signal is amplified many times

over.
A cellular compartment has a change in the
concentration of a specific item.
Proteins are covalently modified.
A membrane potential gradient is altered.

Which of the following INCORRECTLY describes an aspect of

the use of a second messenger in a typical signal transduction
pathway?
The second messenger can diffuse rapidly through the cytosol.
After the rise in the concentration of the second messenger,
it is often removed quickly by degradation or export from the
cytosol.
The proteins that will bind the second messenger are already
present before there is a rise in its concentration.
Synthesis of the enzyme that creates the second
messenger occurs right after the signal is received, and not
before.

When the cell does not receive the signal, the second
messenger is kept at a low concentration.

Which of the following INCORRECTLY describes an aspect of

the use of a second messenger in a typical signal transduction
pathway?
The second messenger can diffuse rapidly through the cytosol.
After the rise in the concentration of the second messenger,
it is often removed quickly by degradation or export from the
cytosol.
The proteins that will bind the second messenger are already
present before there is a rise in its concentration.
Synthesis of the enzyme that creates the second
messenger occurs right after the signal is received, and not
before.

When the cell does not receive the signal, the second
messenger is kept at a low concentration.

Which of the following will most likely be needed

to turn OFF a phosphorylation cascade in a cell's
cytosol after it has been used?
the production of new proteins by the expression
of genes that have just been turned on
the hydrolysis of GTP by an activated G protein
the removal of Ca2+ out of the cytosol by
Ca2+-pumping ATPases
the degradation of inositol triphosphate (IP3) by an
enzyme
the action of specific protein phosphatases

Which of the following will most likely be needed

to turn OFF a phosphorylation cascade in a cell's
cytosol after it has been used?
the production of new proteins by the expression
of genes that have just been turned on

the hydrolysis of GTP by an activated G protein

the removal of Ca2+ out of the cytosol by
Ca2+-pumping ATPases
the degradation of inositol triphosphate (IP3) by
an enzyme

the action of specific protein phosphatases

Which of the following INCORRECTLY describes

something about the signal-transduction response
system shown in the figure on the next slide?
This allows one external signal molecule to induce a large
effect in the cell.
The kinases do their phosphorylations by taking
phosphates from ATPs.
Eventually, the G proteins will cleave their GTP and
become inactive.
To recover and remove the cyclic AMP, phosphodiesterase
is needed.
This system increases the expression of the gene for the
adenylyl cyclase enzyme.

Which of the following INCORRECTLY describes

something about the signal-transduction response
system shown in the figure on the next slide?
This allows one external signal molecule to induce a large
effect in the cell.
The kinases do their phosphorylations by taking
phosphates from ATPs.
Eventually, the G proteins will cleave their GTP and
become inactive.
To recover and remove the cyclic AMP,
phosphodiesterase is needed.
This system increases the expression of the gene for
the adenylyl cyclase enzyme.

For a cell in Caenorhabditis elegans to carry out

apoptosis properly depends in part on
a protein that normally inhibits the process being
turned off.

the creation of a death signal by this cell.

properly resetting all the transductive elements
from the last use of this process.
the receptor moving the
death signal into the nucleus
of the cell.
turning off various nucleases
and proteases in the cell.

For a cell in Caenorhabditis elegans to carry out

apoptosis properly depends in part on
a protein that normally inhibits the process
being turned off.

the creation of a death signal by this cell.

properly resetting all the transductive elements
from the last use of this process.
the receptor moving the
death signal into the nucleus
of the cell.
turning off various nucleases
and proteases in the cell.