Cell Communication

Cell Receptors and Ligands

Department of Medical Physiology

School of Medicine
 The Cellular Internet
• Cell-to-cell communication is essential for
multicellular organisms
• Biologists have discovered some universal
mechanisms of cellular regulation
 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
Cells Communication

• Direct contact
• Paracrine signaling
• Autocrine signalling
• Endocrine signaling
• Synaptic signaling
• Juxtacrine communication
 Direct Contact
• Cells touch each other and signal molecules travel through
special connections called communicating junctions
• Communicating junctions link the cytoplasms of 2 cells together,
permitting the controlled passage of small molecules or ions
between them.

Plasma membranes

Gap junctions Plasmodesmata

between animal cells between plant cells
Cell junctions

Cell-cell recognition
 Cell Communication In Animals
• 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
Local signaling Long-distance signaling

Blood
Target cell Electrical signal Endocrine cell
vessel
along nerve cell
triggers release of
neurotransmitter

Neurotransmitter
Secreting Secretory diffuses across
cell vesicle synapse Hormone travels
in bloodstream
to target cells

Local regulator
diffuses through
extracellular fluid
(a) Paracrine signaling. A secreting cell acts
on nearby target cells by discharging
molecules of a local regulator (a growth
factor, for example) into the extracellular
fluid.
Target cell Target
is stimulated cell
(b) Synaptic signaling. A nerve cell
releases neurotransmitter molecules
into a synapse, stimulating the
target cell.
(c) Hormonal signaling. Specialized
endocrine cells secrete hormones
into body fluids, often the blood.
Hormones may reach virtually all
body cells.
 Autocrine signaling
• In addition, cells secrete chemical messengers that in
some situations bind to receptors on the same cell
• that is, the cell that secreted the messenger (autocrine
communication).
• The chemical messengers include
• Amines
• Amino acids
• Steroids
• Polypeptides, and in some instances, lipids, purine nucleotides,
and pyrimidine nucleotides.
• It is worth noting that in various parts of the body, the
same chemical messenger can function as a
neurotransmitter, a paracrine mediator, a hormone
secreted by neurons into the blood (neural hormone),
and a hormone secreted by gland cells into the blood.
 Juxtacrine communication
• Some cells express multiple repeats of
growth factors such as transforming
growth factor alpha (TGFα)
extracellularly on transmembrane
proteins
• that provide an anchor to the cell.
 Cell Signaling
• The cells of a organism communicate with each other by releasing signal molecules
that bind to receptor proteins located either on or inside of target cells.

• Three stages of cell signaling: Signaling Transduction Pathway (STP)

• Reception - each target cell has receptors that detect a specific signal molecule and binds to
it = 1st messenger = Ligand

• Transduction – binding of the signal molecule changes the receptor protein in some way that
initiates transduction or conversion of the signal to a form that can bring about a specific
cellular response

•
Response – transduced signal triggers a specific cellular response, any cell activity
EXTRACELLULAR CYTOPLASM
FLUID Plasma membrane

1 Reception 2 Transduction 3 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 signal molecule (ligand)
and receptor is highly specific
• A conformational change in a receptor
• Is often the initial transduction of the signal
 Receptors
• Intracellular receptors
• Some signal molecules that are small or hydrophobic can pass through
the plasma membrane and bind to receptors located inside the cell
• Intracellular receptors are cytoplasmic or nuclear proteins

• Cell surface receptors. - Signal molecules that cannot pass through

the plasma membrane bind to receptors located on the surface of
the membrane
 Intracellular Receptors
• Gene Regulators
• Signal molecule joins to the receptor, the receptor
changes shape and a DNA binding site is exposed.
• The DNA binding site joins to a specific segment of
DNA and activates (or suppresses) a particular gene
• Enzyme Receptor
• These receptors function as enzymes – proteins that
catalyze (speed up) specific chemical reactions.
• When a signal molecule joins to the receptor, the
receptor’s catalytic domain is activated (or
deactivated).
Steroid hormone interacting with an intracellular receptor

Hormone EXTRACELLULAR
(testosterone) FLUID 1 The steroid
hormone testosterone
passes through the
plasma membrane.

Plasma
membrane
Receptor 2 Testosterone binds
protein to a receptor protein
in the cytoplasm,
Hormone- activating it.
receptor
complex

3 The hormone-
receptor complex
enters the nucleus
and binds to specific
genes.
DNA

mRNA 4 The bound protein

stimulates the
transcription of
the gene into mRNA.
NUCLEUS New protein

5 The mRNA is
translated into a
specific protein.
CYTOPLASM
 Surface Receptors
• Receptors located on the surface of the membrane, 4 types:
• Chemically gated ion channel receptors
• Enzymatic receptors – Tyrosine kinase
• G-protein-linked receptors
• Integrins
 Chemically Gated Ion Channels
Gate
Gate
Signal close Ions
molecule Closed
• An ion channel (ligand)

receptor acts as a
gate when the Ligand-gated Plasma
receptor changes ion channel receptor Membrane

shape
Gate open
• When a signal
molecule binds as
a ligand to the
receptor, the gate Cellular
allows specific response

ions, such as Na+

or Ca2+, through a Gate close

channel in the
receptor
 Enzymatic Receptors
• Embedded in the plasma membrane, with their catalytic site
exposed inside the cell.
• Catalytic site activated when the signal molecule joins to the
receptor.
• Function as protein kinases (enzymes that phosphorylate
proteins.)
 Receptor Tyrosine Kinases
Signal Signal-binding site
molecule
Signal
 Helix in the molecule
Membrane

Tyr Tyr
Tyr Tyr Tyr Tyr
Tyrosines Tyr Tyr
Tyr Tyr Tyr Tyr
Tyr Tyr
Tyr Tyr Tyr Tyr

Receptor tyrosine
kinase proteins Dimer
CYTOPLASM
(inactive monomers)

Activated
relay proteins

Cellular
Tyr Tyr P Tyr Tyr P P Tyr Tyr P
response 1
Tyr Tyr P Tyr Tyr P P Tyr Tyr P
Tyr Tyr P Tyr Tyr P P Tyr Tyr P Cellular
6 ATP 6 ADP
response 2
Activated tyrosine- Fully activated receptor
kinase regions tyrosine-kinase Inactive
(unphosphorylated (phosphorylated relay proteins
dimer) dimer)
 G-protein-linked Receptors
• Signal molecule joins to a receptor, the receptor activates a G
protein
• The activated G protein can then activate an ion channel or
enzyme in the plasma membrane.

Signal

G-protein-linked receptor

G protein Enzyme or
ion channel
Activated
G protein Activated
enzyme or
ion channel
 Signal-binding site

G-PROTEIN-LINKED RECEPTORS

Segment that
interacts with
G proteins

G-protein-linked Activated Inactive

Plasma Membrane Signal molecule
receptor receptor enzyme

GDP
G-protein GDP GTP
CYTOPLASM (inactive) Enzyme

Activated
enzyme

GTP
GDP
Pi

Cellular response
 Second Messengers
• Some enzymatic receptors
and most G-protein-linked
receptors relay their message
into the cell by activating
other molecules or ions
inside the cell.

• These molecules and ions,

called second messengers,
transmit the message within
the cell. The 2 most common
second messengers are
cAMP and Ca++
• Others are IP3, DAG, PIP
 Signal Transduction Pathways
• Transduction usually involves multiple steps
• Multistep pathways
• Can amplify a signal
• Provide more opportunities for coordination and
regulation
• The molecules that relay a signal from receptor to
response are mostly proteins
• 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
 A Phosphorylation Cascade
• In many pathways, the signal is transmitted by a cascade of protein
phosphorylations - phosphatase enzymes remove the phosphates
• This phosphorylation and dephosphorylation system acts as a molecular switch,
turning activities on and off

Signal molecule

Receptor Activated relay 1 A relay molecule

molecule activates protein kinase 1.

Inactive
protein kinase 2 Active protein kinase 1
1 Active transfers a phosphate from ATP
protein to an inactive molecule of
kinase protein kinase 2, thus activating

Ph
1 this second kinase.

o
sp
Inactive

ho
ATP

ry
protein kinase

lat
2 ADP Active P 3 Active protein kinase 2

io n
protein then catalyzes the phos-

ca
PP kinase phorylation (and activation) of

sc
Pi 2 protein kinase 3.

ad
e
Inactive
protein kinase ATP
3 ADP Active P 4 Finally, active protein
protein kinase 3 phosphorylates a
5 Enzymes called protein kinase
PP protein (pink) that brings
phosphatases (PP) Pi 3 about the cell’s response to
catalyze the removal of
the signal.
the phosphate groups Inactive
from the proteins, protein ATP
ADP P
making them inactive
Active Cellular
and available for reuse.
protein response
PP
Pi
 cAMP Second Messenger
G-protein-signaling pathway
1. Signal molecule binds to First messenger
(signal molecule
surface receptor such as epinephrine) Adenylyl
2. Surface receptor cyclase
activates a G protein G protein
3. G protein activates the
membrane-bound
enzyme, adenylyl
cyclase GTP
G-protein-linked
4. Adenylyl cyclase receptor
catalyzes synthesis of ATP
camp, which binds to a Second
cAMP messenger
target protein
5. Target protein initiates
cellular change Protein
kinase A

Cellular responses
 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

NH2 NH2 NH2

N N N
N N N
O O N N N N O N N
O
Adenylyl cyclase Phoshodiesterase
O P O P O P O Ch2
–
HO P O CH2
CH2
O O O O O O O O O
Pyrophosphate P H2O
P Pi O 
O
OH OH OH OH OH
ATP Cyclic AMP AMP
Cyclic AMP Pathway
 Calcium (Ca++) Pathways
• 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+
ATP pump
Mitochondrion

Nucleus

CYTOSOL

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

Key High [Ca2+] Low [Ca2+]

Calcium ions and Inositol Triphosphate (IP3)
• 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
 Ca++ Pathway
• Signal molecule binds to surface receptor
• Surface receptor activates a G protein
• G protein activates the membrane-bound
enzyme, phospholipase C
• Phospholipase C catalyzes synthesis of
inositol triphosphate, which stimulates
release of Ca++ from ER
• Released Ca++ initiates cellular change
Calcium and IP3 in signaling pathways
1 A signal molecule binds 2 Phospholipase C cleaves a 3 DAG functions as
to a receptor, leading to plasma membrane phospholipid a second messenger
activation of phospholipase C. called PIP2 into DAG and IP3. in other pathways.

EXTRA-
Signal molecule
CELLULAR
(first messenger)
FLUID
G protein

DAG
GTP
G-protein-linked PIP2
receptor Phospholipase C
IP3

IP3-gated
calcium channel

Endoplasmic Various
Cellular
reticulum (ER) Ca 2+ proteins
responses
activated
Ca2+
(second
CYTOSOL messenger)

4 IP3 quickly diffuses through 5 Calcium ions flow out of 6 The calcium ions
the cytosol and binds to an IP3– the ER (down their con- activate the next
gated calcium channel in the ER centration gradient), raising protein in one or more
membrane, causing it to open. the Ca2+ level in the cytosol. signaling pathways.
 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
• Enzyme cascades amplify the cell’s
response
• At each step, the number of activated
products is much greater than in the
preceding step
 Amplification
• Due to the many steps in the cell signaling process, one
signal molecule can trigger a “cascade” effect
Cytoplasmic response to a signal: the stimulation of
glycogen breakdown by epinephrine
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)
 Specificity of Cell Signaling
Signal
• Different kinds of cells have molecule

different collections of Receptor

proteins
• These differences in proteins Relay
molecules

give each kind of cell

specificity in detecting and Response 1 Response 2 Response 3

responding to signals Cell A. Pathway leads

to a single response
Cell B. Pathway branches,
leading to two responses
• The response of a cell to a
signal depends on the cell’s
particular collection of
proteins
• Pathway branching and Activation
or inhibition

“cross-talk” further help the

cell coordinate incoming Response 4 Response 5

signals Cell C. Cross-talk occurs

between two pathways
Cell D. Different receptor
leads to a different response
 Signaling Efficiency: Scaffolding Proteins and
Signaling Complexes
• Rather than relying on diffusion of large relay molecules such as proteins,
many signal pathways are linked together physically by scaffolding
proteins.
• Scaffolding proteins may themselves be relay proteins to which several
other relay proteins attach.
• This hardwiring enhances the speed, accuracy, and efficiency of signal
transfer between cells.

Signal
Plasma
molecule
membrane

Receptor

Three
different
protein
Scaffolding kinases
protein
Figure 11.16
 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
 Receptors for Chemical Messenger
• These proteins are not static components of the cell, but
their numbers increase and decrease in response to
• 1) various stimuli
• 2) their properties change with changes in physiological
conditions.
• When a hormone or neurotransmitter is present in
excess, the number of active receptors generally
decreases (down-regulation).
• desensitization, in which receptors are chemically modified in

ways that make them less responsive.

• Whereas in the presence of a deficiency of the chemical
messenger, there is an increase in the number of active
receptors (up-regulation)