SIGNAL

TRANSDUCTION

DESAK MADE WIHANDANI

DEPT. OF BIOCHEMISTRY
FACULTY OF MEDICINE
UDAYANA UNIVERSITY
Multicellular Organisms have BIG Communication Problems

Hey You divide Oi! We need

now!!! some glucose!

?
Will you
PLEASE stop
dividing!

Come in #7,
your time is up!
 The Solutions

Sorting out the relevant signals from the irrelevant

Receptors with a high degree of specificity

Detecting signals at low concentrations

Receptors with high affinity coupled to an amplification system

Translating diverse signals into a common intracellular

language
 The Solutions

Sorting out the relevant signals from the irrelevant

Receptors with a high degree of specificity

Detecting signals at low concentrations

Receptors with high affinity coupled to an amplification system

Translating diverse signals into a common intracellular

language

Activation of signalling pathways designed around a

limited number of common processes
 What Signals Do

Cells respond to signals in a variety of ways

Altered metabolism e.g. altered glycogen metabolism in

response to insulin

Excitation e.g. propagation of nerve impulse in response to

neurotransmitters

Growth and Division (mitogenesis) in response to peptide

growth factors

Programmed Cell Death caused by specific death factors or

by removal of other essential factors

Altered Gene Expression e.g. immunoglobulin synthesis in

response to cytokine signals
 Local and Long-Distance Signaling
Cells in a multicellular organism 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, or cell-cell recognition

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Figure 11.4
Plasma membranes

Gap junctions Plasmodesmata

between animal cells between plant cells
(a) Cell junctions

(b) Cell-cell recognition

 In many other cases, animal cells communicate
using local regulators, messenger molecules
that travel only short distances
In long-distance signaling, animals use
chemicals called hormones
The ability of a cell to respond to a signal
depends on whether or not it has a receptor
specific to that signal

2011 Pearson Education, Inc.

 Figure 11.5

Local signaling Long-distance signaling

Target cell Electrical signal Endocrine cell

along nerve cell Blood
triggers release of vessel
neurotransmitter.

Neurotransmitter
Secreting Secretory diffuses across
cell vesicle synapse.
Hormone travels
in bloodstream.

Target cell
Local regulator specifically
diffuses through Target cell binds
extracellular fluid. is stimulated. hormone.

(a) Paracrine signaling (b) Synaptic signaling

(c) Endocrine (hormonal) signaling

 SIGNAL TRANSDUCTION

Allow the cell to sense and respond to

signals in the environment and to change
their behavior accordingly

Signals are sensed by a receptor and

change in their form, so that they can
exert their final effect on the cell
DEFINITION

Signal
Receptor
Second messenger
 SIGNALS

Any small molecules that binds specifically

to a receptor site
Start the whole thing
Signal is what the target cell senses
 SIGNALS
Signals start everything
Signals that enter the cell
- Hydrophobic
- Steroids, Vit.D, thyroid hormone and retinoids
- Half-life: hours-days

Signals that exert their effects from outside the cell

- Hydrophylic
- Insulin, glucagon, growth factors
- Half-life: seconds-minutes
 RECEPTORS
Sense the signal and are activated.
Sensing the signal causes a change in the
structure of the receptor
Receptors recognize a signal molecule
and transmit the signal by activating a
downstream signaling pathway
The same signal often has a different
effect on different cell types
 RECEPTORS

1. Intracellular/cytosolic receptors
2. Extracellular/ transmembrane/cell
surface membrane receptors
 INTRACELLULAR RECEPTORS
The signal crosses the membrane and activates gene
transcription.
Intracellular receptor proteins are 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
Figure 11.9-1
Hormone EXTRACELLULAR
(testosterone) FLUID

Plasma
membrane
Receptor
protein

DNA

NUCLEUS

CYTOPLASM
Figure 11.9-2
Hormone EXTRACELLULAR
(testosterone) FLUID

Plasma
membrane
Receptor
protein
Hormone-
receptor
complex

DNA

NUCLEUS

CYTOPLASM
Figure 11.9-3
Hormone EXTRACELLULAR
(testosterone) FLUID

Plasma
membrane
Receptor
protein
Hormone-
receptor
complex

DNA

NUCLEUS

CYTOPLASM
Figure 11.9-4
Hormone EXTRACELLULAR
(testosterone) FLUID

Plasma
membrane
Receptor
protein
Hormone-
receptor
complex

DNA

mRNA

NUCLEUS

CYTOPLASM
Figure 11.9-5
Hormone EXTRACELLULAR
(testosterone) FLUID

Plasma
membrane
Receptor
protein
Hormone-
receptor
complex

DNA

mRNA

NUCLEUS
New protein

CYTOPLASM
EXTRACELLULAR/TRANSMEMBRANE
RECEPTORS/CELL-SURFACE
MEMBRANE RECEPTORS

Signals that do not enter the cell must be

sensed by a receptor outside that can send the
signal inside. These signals are sensed by
Transmembrane receptors
Polypeptide hormones (Insulin, glucagon, growth
hormones)
As first messenger
Second messenger
TRANSMEMBRANE RECEPTORS/ CELL-
SURFACE MEMBRANE RECEPTORS

These receptors span the membrane.

3 large classes of cell surface
receptors; ion channel, a G-protein
linked receptors or an enzyme linked
receptors
 ION-CHANNEL COUPLED
RECEPTORS
A ligand-gated 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
The signal activates the flow of ions across the membrane
 Figure 11.7d

1 2 3

Gate
closed Ions Gate Gate closed
Signaling open
molecule
(ligand)

Plasma
Ligand-gated
membrane
ion channel receptor Cellular
response
G-PROTEIN COUPLED RECEPTORS

These activate a G-protein that activates

downstream signals
G-protein activation usually leads to an
increase in second messenger
concentration
G-protein linked receptor
G-PROTEIN COUPLED RECEPTORS

G-protein-coupled receptor (GPCRs)

are the largest family of cell-surface
receptors
A GPCR 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
 G-proteins
Heterotrimeric G-protein consists of three
subunits: , and
subunit is effector specificity and
contains the GTP-binding site and an
intrinsic GTP-ase activity
Four major subfamilies of -subunit
genes, the most common Gs and Gi
Without signaling molecule G-
protein is inactive
G-protein binds to receptor when signaling
molecule is present
Reassembly of subunit with other 2 subunits
reforms inactive G-protein complex
 Figure 11.7b

G protein-coupled Plasma Activated Signaling Inactive

receptor membrane receptor molecule enzyme

GTP
GDP GDP
CYTOPLASM
G protein Enzyme GDP GTP
1 (inactive) 2

Activated
enzyme

GTP
GDP
Pi

3 Cellular response 4
ENZYME COUPLED RECEPTORS
Signal activates an enzyme activity of the
receptor itself
Activation of the receptor turns the
receptor itself into an active enzyme
Tyrosine kinase: phosphorylate protein
tyrosine residue
Phospholipase C: cleaves PIP2 into IP3
and DAG
 Small Molecules and Ions as
Second Messengers
The extracellular signal molecule (ligand) that
binds to the receptor is a pathways first
messenger
Second messengers are small, nonprotein, water-
soluble molecules or ions that spread throughout a
cell by diffusion
Second messengers participate in pathways
initiated by GPCRs and RTKs
Cyclic AMP and calcium ions are common second
messengers
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 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

2011 Pearson Education, Inc.

Figure 11.11a

Adenylyl cyclase

Pyrophosphate
P Pi

ATP cAMP
 Many signal molecules trigger formation of cAMP
Other components of cAMP pathways are G
proteins, G protein-coupled 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
Figure 11.12

First messenger
(signaling molecule
such as epinephrine)
Adenylyl
G protein cyclase

G protein-coupled GTP
receptor

ATP
Second
cAMP messenger

Protein
kinase A

Cellular responses
Activation of gene transcription by
cAMP
 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

2011 Pearson Education, Inc.

Figure 11.13
EXTRACELLULAR Plasma
FLUID membrane

Ca2
ATP pump
Mitochondrion

Nucleus

CYTOSOL

Ca2
pump
Endoplasmic
Ca2 reticulum
ATP pump (ER)

Key High [Ca2 ] Low [Ca2 ]

 Figure 11.14-1

EXTRA-
CELLULAR Signaling molecule
FLUID (first messenger)

G protein

DAG
GTP
G protein-coupled PIP2
Phospholipase C
receptor
IP3
(second messenger)

IP3-gated
calcium channel

Endoplasmic Ca2
reticulum (ER)

CYTOSOL
 Figure 11.14-2

EXTRA-
CELLULAR Signaling molecule
FLUID (first messenger)

G protein

DAG
GTP
G protein-coupled PIP2
Phospholipase C
receptor
IP3
(second messenger)

IP3-gated
calcium channel

Endoplasmic Ca2
reticulum (ER)
Ca2
(second
CYTOSOL messenger)
 Figure 11.14-3

EXTRA-
CELLULAR Signaling molecule
FLUID (first messenger)

G protein

DAG
GTP
G protein-coupled PIP2
Phospholipase C
receptor
IP3
(second messenger)

IP3-gated
calcium channel

Various Cellular
Endoplasmic Ca2
proteins
reticulum (ER) responses
activated
Ca2
(second
CYTOSOL messenger)
Figure 11.16
Reception
Binding of epinephrine to G protein-coupled 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 (10 5)

Inactive glycogen phosphorylase

Active glycogen phosphorylase (10 6)

Response
Glycogen
Glucose 1-phosphate
(108 molecules)