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
  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

© 2011 Pearson Education, Inc.

Modes of cell-cell signaling

1. Direct cell-cell or cell-matrix (integrins and cadherins)

2. Indirect: Secreted molecules.

A. Endocrine signaling. The signaling molecules are

hormones secreted by endocrine cells and carried through
the circulation system to act on target cells at distant body
sites.

B. Paracrine signaling. The signaling molecules released by

one cell act on neighboring target cells (neurotransmitters).

C. Autocrine signaling. Cells respond to signaling molecules

that they themselves produce (response of the immune
system to foreign antigens and cancer cells).
 Plasma membranes

Gap junctions Plasmodesmata

between animal cells between plant cells
(a) Cell junctions

(b) Cell-cell recognition

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

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
 Signal transduction within cells is accomplished by
combinations of:
 1st Messenger (extracellular signals e.g. epinephrine,
acetylcholine)
 Receptor

 Effectors (e.g. adenylyl cyclase, phospholipases, kinases,

ion channels etc)
 2nd messengers (cAMP, cGMP, inositol triphosphate,
diacylgycerol, Ca2+ etc)
 Downstream effectors required for specific functional
outputs (e.g. muscle contraction, secretion)
Specificity results from:
 Differential expression and localization of receptors

 Different receptors couple to different signal transducers

 Signal transducers/2nd messengers couple to different effectors in different tissues

  Signal
 Receptor
 Second messenger
 Any small molecules that binds specifically to a
receptor site
 Start the whole thing
 Signal is what the target cell senses
 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
 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
 A signaling molecule binds to a receptor
protein, causing it to change shape
 The binding between a signal molecule
(ligand) and receptor is highly specific
 A shape change in a receptor is often the
initial transduction of the signal
 Most signal receptors are plasma
membrane proteins
1. Intracellular/cytosolic receptors
2. Extracellular/ transmembrane/cell surface
membrane 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
Hormone EXTRACELLULAR
(testosterone) FLUID

Plasma
membrane
Receptor
protein

DNA

NUCLEUS

CYTOPLASM
Hormone EXTRACELLULAR
(testosterone) FLUID

Plasma
membrane
Receptor
protein
Hormone-
receptor
complex

DNA

NUCLEUS

CYTOPLASM
Hormone EXTRACELLULAR
(testosterone) FLUID

Plasma
membrane
Receptor
protein
Hormone-
receptor
complex

DNA

NUCLEUS

CYTOPLASM
Hormone EXTRACELLULAR
(testosterone) FLUID

Plasma
membrane
Receptor
protein
Hormone-
receptor
complex

DNA

mRNA

NUCLEUS

CYTOPLASM
Hormone EXTRACELLULAR
(testosterone) FLUID

Plasma
membrane
Receptor
protein
Hormone-
receptor
complex

DNA

mRNA

NUCLEUS
New protein

CYTOPLASM
 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
 These receptors span the
membrane.
 3 large classes of cell surface
receptors; ion channel, a G-
protein linked receptors or an
enzyme linked 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
1 2 3

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

Plasma
Ligand-gated
membrane
ion channel receptor Cellular
response
 These activate a G-protein that activates
downstream signals
 G-protein activation usually leads to an
increase in second messenger concentration
 Regulate a wide variety of biological
processes, such as vision, olfaction, the
autonomic nervous system, and behavior.
 Play a role in the pathophysiology of many
diseases
 Heterotrimeric G-protein consists of three
subunits: α, β and γ
 α subunit is effector specificity and contains
the GTP-binding site and an intrinsic GTP-ase
activity
 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
 Ligand: Peptide and non-peptide hormones and
neurotransmitters, chemokines, prostanoids
and proteinases, biogenic amines, nucleosides,
lipids, growth factors, odorant molecules and
light
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
 Adenosine Diphosphate Ribosylation of G-
Proteins
 Cholera
 Pertussis.
 Diphtheria

 Erectile Dysfunction
 GPCR/G protein-mediated signalling impacts
oncogenesis at multiple levels by regulating
tumour angiogenesis, immune evasion,
metastasis, and drug resistance
 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
47
  The extracellular signal molecule (ligand) that
binds to the receptor is a pathway’s “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
© 2011 Pearson Education, Inc.
  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.

 Adenylyl cyclase Phosphodiesterase

Pyrophosphate H2O
P Pi

ATP cAMP AMP

 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
 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
  Calcium ions (Ca2+) act as a second messenger in many
pathways
 Calcium is an important second messenger because cells can
regulate its concentration
 Calcium cellular concentration is maintained low by pumps
that transport calcium across the plasma membrane and from
the cytosol inside the endoplasmic reticulum (ER).
 High concentrations of calcium activate the functions of
proteins including protein kinase and phosphatases.

© 2011 Pearson Education, Inc.

EXTRACELLULAR Plasma
FLUID membrane

Ca2
ATP pump
Mitochondrion

Nucleus

CYTOSOL

Ca2
pump
Endoplasmic
Ca2 reticulum
ATP pump (ER)

Key High [Ca2 ] Low [Ca2 ]

 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
 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)
 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)
60
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 (10 2)

ATP
Cyclic AMP (104)

Inactive protein kinase A

Active protein kinase A (10 4)

Inactive phosphorylase kinase

Active phosphorylase kinase (10 5)

Inactive glycogen phosphorylase

Active glycogen phosphorylase (10 6)

Response
Glycogen
Glucose 1-phosphate
(108 molecules)