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

2. Cell Communication Ch 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
Exchange of
mating factors
a factor
Receptor
Exchange of mating factors- Each cell type secretes a mating factor that binds to receptors on the other cell type
Mating- Binding of the factors to receptors induces changes in the cells that lead to their fusion
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 cell’s surface is converted into a specific cellular response
Signal transduction pathways convert signals on a cell’s 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. Gap junctions between animal cells Plasmodesmata between plant cells
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. Local signaling
Long-distance signaling
Target cell
Electrical signal
along nerve cell
triggers release of
neurotransmitter
Endocrine cell
Blood
vessel
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
(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.
(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:
Reception: Detection of a signal molecule (ligand) coming from outside the cell
Transduction: Convert signal to a form that can bring about a cellular response
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 cell’s surface or inside the cell

12. Relay molecules in a signal transduction
EXTRACELLULAR
FLUID
CYTOPLASM
Plasma membrane
Reception
Transduction
Receptor
Relay molecules in a signal transduction
pathway
Signal
molecule
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.

13. Relay molecules in a signal transduction
EXTRACELLULAR
FLUID
CYTOPLASM
Plasma membrane
Reception
Transduction
Response
Receptor
Activation
of cellular
response
Relay molecules in a signal transduction
pathway
Signal
molecule
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.

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. EXPLANATION OF STEPS ON PREVIOUS SLIDE
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 receptor 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 When the ligand dissociates from this receptor, the gate closes and ions no longer enter the cell.
Signal
molecule
(ligand)
Gate
closed
Ions
Plasma
membrane
Ligand-gated
ion channel receptor
Gate open
Cellular
response
Gate closed

23. Plasma Membrane Receptors Overview
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. Steroid hormone interacting with an intracellular receptor
LE 11-6
Hormone
(testosterone)
EXTRACELLULAR
FLUID
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
mRNA
The bound protein
stimulates the
transcription of
the gene into mRNA.
NUCLEUS
New protein
The mRNA is
translated into a
specific protein.
CYTOPLASM

26. 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

28. 1. A relay molecule activates protein kinase 1
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
Active
protein
kinase 2 P 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 cell’s response to the signal
Inactive
protein kinase 3
ATP
ADP
Active
protein
kinase 3 P PP P i
Inactive
protein
ATP
ADP P
Active
protein
Cellular
response 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 pathway’s “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. The maintenance of calcium ion concentrations in an animal cell.
LE 11-11
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.
EXTRACELLULAR
FLUID
Plasma
membrane
Ca2+
pump
ATP
Mitochondrion
Nucleus
CYTOSOL
Ca2+
pump
Endoplasmic
reticulum (ER)
ATP
Ca2+
pump
Key
High [Ca2+]
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. EXTRACELLULAR Signal molecule FLUID (first messenger) G protein DAG
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. EXTRACELLULAR Signal molecule FLUID (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

38. EXTRACELLULAR Signal molecule FLUID (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 cell’s 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
Cell A. Pathway leads
to a single response
Cell B. Pathway branches,
leading to two responses
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 (Parkinson’s, Alzheimer’s)

47. Apoptosis of a human white blood cell
Figure Apoptosis of human white blood cells
Left: Normal WBC
Right: WBC undergoing apoptosis – shrinking and forming lobes (“blebs”)

48. Effect of apoptosis during paw development in the mouse
Figure Effect of apoptosis during paw development in the mouse