Warm-Up

1
Warm-Up

1. Why do you communicate?
2. How do you communicate?
3. How do you think cells communicate?
4. Do you think bacteria can communicate? Explain.
5. Compare the structure function of these
   receptor proteins GPCR, tyrosine kinase and
   ligand-gated ion channels.
6. What is a second messenger? What are some
   examples of these molecules?
7. What are the possible responses to signal
   transduction in a cell?

2
Cell CommunicationCh 11

• What you should know
• The 3 stages of cell communication reception,
  transduction, and response.
• How G-protein-coupled receptors receive signals
  and start transduction.
• How receptor tyrosine kinase receive cell signals
  and start transduction.
• How a cell signal is amplified by a
  phosphorylation cascade.
• How a cell response in the nucleus turns on genes
  while in the cytoplasm it activates enzymes.
• What apoptosis means and why it is important to
  normal functioning of multicellular organisms.

3
External signals are converted into responses
within the cell

• What does a talking cell say to a listening
  cell, and how does the latter cell respond to the
  message?
• Microbes are a window on the role of cell
  signaling in the evolution of life
• One topic of cell conversation is sex. An
  example would be yeast (used for making beer,
  wine, and bread). Yeast cells identify their
  mates by chemical signaling.

4
Communication between mating yeast cells
a factor
Exchange of mating factors
Receptor

1. Exchange of mating factors- Each cell type
   secretes a mating factor that binds to receptors
   on the other cell type
2. Mating- Binding of the factors to receptors
   induces changes in the cells that lead to their
   fusion
3. New cell- The nucleus is a fused cell that
   includes all the genes from the original cells

a
a
a factor
Yeast cell, mating type a
Yeast cell, mating type a
Mating
a
a
New a/a cell
a/a
5
Evolution of Cell Signaling

• A signal-transduction pathway is a series of
  steps by which a signal on a cells surface is
  converted into a specific cellular response
• Signal transduction pathways convert signals on a
  cells surface into cellular responses
• Pathway similarities suggest that ancestral
  signaling molecules evolved in prokaryotes and
  have since been adopted by eukaryotes

6
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

7
Cell Signaling

• Animal cells communicate by
• Direct contact (gap junctions)
• Secreting local regulators (growth factors,
  neurotransmitters)
• Long distance (hormones)

8
Communication by direct contact between
cells(a) Cell Junctions- Both animals and
plants have cell junctions that allow molecules
to pass readily between adjacent cells without
crossing plasma membranes.(b) Cell-Cell
recognition- Two cells in an animal may
communicate by interaction between molecules
protruding from their surfaces.
Plasma membranes
Gap junctions between animal cells
Plasmodesmata between plant cells
Cell junctions
Cell-cell recognition
9
(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.
Local signaling
Long-distance signaling
Target cell
Endocrine cell
Blood vessel
Electrical signal along nerve cell triggers
release of neurotransmitter
Neurotransmitter diffuses across synapse
Secreting cell
Secretory vesicle
Hormone travels in bloodstream to target cells
Local regulator diffuses through extracellular
fluid
Target cell
Target cell is stimulated
Paracrine signaling
Synaptic signaling
Hormonal signaling
(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
10
3 Stages of Cell Signaling

1. Reception Detection of a signal molecule
   (ligand) coming from outside the cell
2. Transduction Convert signal to a form that can
   bring about a cellular response
3. Response Cellular response to the signal
   molecule

11
EXTRACELLULAR FLUID
CYTOPLASM
Plasma membrane
Reception
Transduction
Receptor
Signal molecule
1. Reception- Reception is the target cells
detection of a signal molecule coming from
outside the cell. A chemical signal is detected
when it binds to a receptor protein located at
the cells surface or inside the cell
12
2. Transduction- The binding of the signal
molecule changes the receptor protein in some
way, initiating the process of transduction. The
transduction stage converts the signal to a form
that can bring about the specific cellular
response. Transduction sometimes occurs in a
single step but more often requires a sequence of
changes in a series of different molecules- a
signal transduction pathway. The molecules in the
pathway are often called relay molecules.
EXTRACELLULAR FLUID
CYTOPLASM
Plasma membrane
Reception
Transduction
Receptor
Relay molecules in a signal transduction pathway
Signal molecule
13
3. Response- In the third stage of cell
signaling, the transduced signal finally triggers
a specific cellular response. The response may be
almost any imaginable cellular activity- such as
catalysis by an enzyme, rearrangement of the
cytoskeleton, or activation of specific genes in
the nucleus.The cell signaling process helps
ensure that crucial activities like these occur
in the right cells, at the right time, and in
proper coordination with the other cells of the
organism.
EXTRACELLULAR FLUID
CYTOPLASM
Plasma membrane
Reception
Transduction
Response
Receptor
Activation of cellular response
Relay molecules in a signal transduction pathway
Signal molecule
14
1. Reception

• Binding between signal molecule (ligand)
  receptor is highly specific.
• Types of Receptors
• Plasma membrane receptor
• water-soluble ligands
• Intracellular receptors (cytoplasm, nucleus)
• hydrophobic or small ligands
• Eg. testosterone or nitric oxide (NO)
• Ligand binds to receptor protein ? protein
  changes SHAPE ? initiates transduction signal

15
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

16
G-Protein-Coupled Receptor

• 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
• These are extremely widespread and diverse in
  their functions, including roles in embryonic
  development and sensory reception
• They are also involved in many human diseases,
  including bacterial infections. Up to 60 of all
  medicines used today exert their effects by
  influencing G-protein pathways

17
G-Protein-Coupled Receptor
18
Receptor Tyrosine Kinase

• Receptor tyrosine kinases are membrane receptors
  that attach phosphates to tyrosines
• A receptor tyrosine kinase can trigger multiple
  signal transduction pathways at once

19
Receptor Tyrosine Kinase
20
1. Many receptor tyrosine kinases have the
structure depicted schematically here. Before
the signal molecule binds, the receptors exist as
individual polypepitides. Notice that each has an
extracellular signal-binding site, and alpha
helix spanning the membrane, an intracellular
tail containing multiple tyrosines.
2. The binding of a signal molecule (such as a
growth factor) causes two receptor polypeptides
to associate closely with each other, forming a
dimer (dimerization)
4. Now that the receptor protein is fully
activated, it is recognized by specific relay
proteins inside the cell. Each such protein binds
to a specific phosphorylated tyrosine, undergoing
a resulting structural change that activates the
bound protein. Each activated protein triggers a
transduction pathway, leading to a cellular
response.
3. Dimerization activates the tyrosine-kinase
region of each polypeptide each tyrosine kinase
adds a phosphate from an ATP molecule to a
tyrsine on the tail of the other polypeptide.
EXPLANATION OF STEPS ON PREVIOUS SLIDE
21
Ligand-Gated Ion Channel

• 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

22
1. Here we show a ligand-gated ion channel
receptor in which the gate remains closed until a
ligand binds to the receptor2. When the
ligand binds to the receptor and the gate opens,
specific ions can flow through the channel and
rapidly change the concentration of that
particular ion inside the cell. This change may
directly affect the activity of the cell in some
way.3. When the ligand dissociates from this
receptor, the gate closes and ions no longer
enter the cell.
Gate closed
Signal molecule (ligand)
Ions
Plasma membrane
Ligand-gated ion channel receptor
Gate open
Cellular response
Gate closed
23
Plasma Membrane ReceptorsOverview
G-Protein Coupled Receptor (GPCR) Tyrosine Kinase Ligand-Gated Ion Channels
7 transmembrane segments in membrane Attaches (P) to tyrosine Signal on receptor changes shape
G protein GTP activates enzyme ? cell response Activate multiple cellular responses at once Regulate flow of specific ions (Ca2, Na)
24
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

25
LE 11-6
EXTRACELLULAR FLUID
Hormone (testosterone)
The steroid hormone testosterone passes
through the plasma membrane.
Steroid hormone interacting with an intracellular
receptor
Plasma membrane
Testosterone binds to a receptor protein in
the cytoplasm, activating it.
Receptor protein
Hormone- receptor complex
The hormone- receptor 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
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2. Transduction

• Cascades of molecular interactions relay signals
  from receptors ? target molecules
• Protein kinase enzyme that phosphorylates and
  activates proteins at next level
• Phosphorylation cascade enhance and amplify
  signal
• These multistep pathways provide more
  opportunities for coordination and regulation

27
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
• 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

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LE 11-8
Signal molecule
1. A relay molecule activates protein kinase 1
Receptor
Activated relay molecule
2. Active protein kinase 1 transfers a phosphate
from ATP to an inactive molecule of protein
kinase 2, thus activating this second kinase
Inactive protein kinase 1
Active protein kinase 1
3. Active Protein kinase 2 then catalyzes the
phosphorylation (and activation) of protein
kinase 3
Phosphorylation cascade
Inactive protein kinase 2
ATP
ADP
P
Active protein kinase 2
PP
P
i
5. Enzymes called protein phosphatases (PP)
catalyze the removal of phosphate groups from the
proteins, making them inactive and available for
reuse.
4. Finally, active protein kinase 3
phosphorylates a protein (pink) that brings about
the cells response to the signal
Inactive protein kinase 3
ATP
ADP
P
Active protein kinase 3
PP
P
i
Inactive protein
ATP
P
ADP
Cellular response
Active protein
PP
P
i
29
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

30
Second Messengers

• small, nonprotein molecules/ions that can relay
  signal inside cell
• Second messengers participate in pathways
  initiated by G-protein-linked receptors and
  receptor tyrosine kinases
• Eg. cyclic AMP (cAMP), calcium ions (Ca2),
  inositol triphosphate (IP3)

31
Cyclic AMP

• Cyclic AMP (cAMP) is one of the most widely used
  second messengers
• The second messenger cyclic AMP (cAMP) is made
  from ATP by adenylyl cyclase, an enzyme embedded
  in the plasma membrane. Cyclic AMP is inactivated
  by phosphodiesterase, an enzyme that converts it
  to AMP

32
cAMP

• cAMP cyclic adenosine monophosphate
• GPCR ? adenylyl cyclase (convert ATP ? cAMP) ?
  activate protein kinase A

cAMP as a second messenger in a
G-protein-signaling pathway. The first messenger
activates a G-protein-linked receptor, which
activates a specific G protein. In turn, the G
protein activates adenylyl cyclase, which
catalyzes the conversion of ATP to cAMP. The cAMP
then activates another protein, usually protein
kinase A
33
Second Messengers- Calcium ions

• Calcium ions (Ca2) act as a second messenger in
  many pathways
• Calcium is an important second messenger because
  cells can regulate its concentration

34
LE 11-11
EXTRACELLULAR FLUID
The maintenance of calcium ion concentrations in
an animal cell. The calcium concentration in the
cytosol is usually lower than in the
extracellular fluid and ER. Protein pumps in the
plasma membrane and the ER membrane, driven by
ATP, move calcium from the cytosol into the
extracellular fluid and into the lumen of the ER.
Mitochondrial pumps, driven by chemiosmosis, move
calcium into the mitochondria when the calcium
level in the cytosol rises significantly.
Plasma membrane
Ca2 pump
ATP
Mitochondrion
Nucleus
CYTOSOL
Ca2 pump
Endoplasmic reticulum (ER)
ATP
Ca2 pump
High Ca2
Key
Low Ca2
35
Second Messengers- Inositol Triphosphate (IP3)

• 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

36
LE 11-12_1
2. Phospholipase C cleaves a plasma membrane
phospholipid called PIP2 into DAG and IP3
DAG functions as a second messenger in other
pathways
EXTRACELLULAR FLUID
Signal molecule (first messenger)
1. A signal molecule binds to a receptor,
leading to activation of phospholipase C
G protein
DAG
GTP
G-protein-linked receptor
PIP2
Phospholipase C
IP3 (second messenger)
IP3-gated calcium channel
Endoplasmic reticulum (ER)
Ca2
4. IP3 quickly diffuses through the cytosol and
binds to an IP3 gated calcium channel in the ER
membrane, causing it to open
CYTOSOL
37
LE 11-12_2
EXTRACELLULAR FLUID
Signal molecule (first messenger)
G protein
DAG
GTP
G-protein-linked receptor
PIP2
Phospholipase C
IP3 (second messenger)
IP3-gated calcium channel
5. Calcium ions flow out of the ER (down the
concentration gradient), raising the calcium
level in the cytosol
Endoplasmic reticulum (ER)
Ca2
Ca2 (second messenger)
CYTOSOL
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LE 11-12_3
EXTRACELLULAR FLUID
Signal molecule (first messenger)
G protein
DAG
GTP
G-protein-linked receptor
PIP2
Phospholipase C
IP3 (second messenger)
IP3-gated calcium channel
Cellular re- sponses
Various proteins activated
Endoplasmic reticulum (ER)
Ca2
Ca2 (second messenger)
6. The calcium ions activate the next protein in
one or more signaling pathways
CYTOSOL
39
3. Response

• Regulate protein synthesis by turning on/off
  genes in nucleus (gene expression)
• Regulate activity of proteins in cytoplasm
• 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

40
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

41
LE 11-15
Signal molecule
Receptor
Relay molecules
Response 1
Response 2
Response 3
Cell B. Pathway branches, leading to two responses
Cell A. Pathway leads to a single response
Activation or inhibition
Response 4
Response 5
Cell C. Cross-talk occurs between two pathways
Cell D. Different receptor leads to a different
response
42
Signal Transduction Pathway Problems/Defects

• Examples
• Diabetes
• Cholera
• Autoimmune disease
• Cancer
• Neurotoxins, poisons, pesticides
• Drugs (anesthetics, antihistamines, blood
  pressure meds)

43
Cholera

• Toxin modifies G-protein involved in regulating
  salt water secretion
• G protein stuck in active form ? intestinal cells
  secrete salts, water
• Infected person develops profuse diarrhea and
  could die from loss of water and salts

• Disease acquired by drinking contaminated water
  (w/human feces)
• Bacteria (Vibrio cholerae) colonizes lining of
  small intestine and produces toxin

44
Viagra

• Used as treatment for erectile dysfunction
• Inhibits hydrolysis of cGMP ? GMP
• Prolongs signal to relax smooth muscle in artery
  walls increase blood flow to penis

45
Viagra inhibits cGMP breakdown
46
Apoptosis cell suicide

• Cell is dismantled and digested
• Triggered by signals that activate cascade of
  suicide proteins (caspase)
• Why?
• Protect neighboring cells from damage
• Animal development maintenance
• May be involved in some diseases (Parkinsons,
  Alzheimers)

47
Apoptosis of a human white blood cell

• Left Normal WBC
• Right WBC undergoing apoptosis shrinking and
  forming lobes (blebs)

48
Effect of apoptosis during paw development in the
mouse