The document provides an overview of signal transduction and cell signaling pathways. It discusses (1) signaling molecules that bind to membrane receptors, (2) intracellular signaling cascades involving second messengers like cAMP and IP3, and (3) how cells amplify and terminate signals. The summary concludes with questions to test the reader's understanding of key concepts.

1. Biomembrane Signal
Transduction
Done by:
Abdallah M. Youssof
PhD Student, College of
Pharmacy, KSU
ayoussof@ksu.edu.sa

2. OUTLINES
I. Overview of cell signaling
II. Signaling molecules
III. Receptors for signaling molecules
IV. Signaling proteins
V. Second messenger systems
VI. Conclusions
VII. Questions
2

3. I. Overview of Cell Signaling:
Signal transduction: the ability of cell to translate
receptor-ligand interaction into a change in behavior or
gene expression.
• Signaling pathways regulate nearly all cellular
functions.
• A cell in a multicellular organism may be exposed to
hundreds of signals.
• Different types of cells respond differently to the
same type of signals. 3

4. I. Overview of Cell Signaling:
Method used by cells to communicate
I. Cell-Cell communication
II. Cell Signaling (using chemical messengers):
A. Local Signaling (Over short distances):
• Cell-Cell Recognition (contact-dependent)
ex. delta/notch signaling
4

5. I. Overview of Cell Signaling:
Method used by cells to communicate
• Local regulators:
- Paracrine (growth factors)
- Synaptic (neurotransmitters)
5

6. I. Overview of Cell Signaling:
Method used by cells to communicate
B. Long distance signaling:
• Endocrine (Ex. Hormones)
6

7. I. Overview of Cell Signaling:
Three stages of signal transduction
1⁰ry
Messengers
2⁰ry
Messengers
Target
Enzymes
7

8. I. Overview of Cell Signaling:
Three stages of signal transduction
Signal triggers receptor
Receptor triggers internal signaling proteins/2⁰ry messe
Secondary messengers trigger effector proteins/target e
Response
Cascade/
Amplification
Effect
8

9. I. Overview of Cell Signaling:
Specific Responses of Cells to
Signaling
• Survive
• Grow / Divide
• Differentiate
• Die
9

10. I. Overview of Cell Signaling:
The response can be fast or
slow
• Different pathways have
different rates of response.
• Pathways involve gene
expression regulation are
10

11. I. Overview of Cell Signaling:
• Each protein in a signaling pathway Amplifies the signal by activating
multiple copies of the next component in the pathway:
- 1 Primary enzyme activates 100 target enzymes
The concept of AMPLIFICATION
- Each of the 100 enzymes activates an additional 100 dowstream target enzymes
- Each of the 10,000 downstream target enzyme activates 100 control factors
so rapidly have
1,000,000 active control factors
11

12. I. Overview of Cell Signaling:
12

13. II. Signaling Molecules:
 Small molecules
 Peptides
 Proteins
 LIGANDS
- Ligands alter receptor structure - conformational
change => activation of the receptor
- Once a ligand is released, the receptor is no longer
activated
13

14. III. Receptors for Signal Molecules:
A- Intracellular Receptors
• Located inside the cell; either
in the nucleus (nuclear
receptors) or on the ER (ex.
IP3).
• Bind to hydrophobic Signal
molecules such as thyroid and
steroid hormones.
• Examples of intracellular
receptors: light and gas
A-
14

15. III. Receptors for Signal Molecules:
B. Membrane Receptors
• Bind to hydrophilic signal
molecules
E.g. peptide hormones
(Most receptors are at the cell
surface)
B-
15

16. III. Receptors for Signal Molecules:
B- Membrane Receptors (located on the cell
membrane)
• Very important in the
nervous system
• Signal triggers the opening
of an ion channel by
depolarization
• Triggered by
neurotransmitters
• Gated ion channels:
specifically let ions through
membrane by;
- small molecules (ligand-
gated)
1-
16

17. III. Receptors for Signal Molecules:
B- Membrane Receptors
2-
17

18. G-protein
activation“molecular switch”
(b) Ligand binds and G-protein
associates
(c) GDP-GTP exchange and -
Subunit dissociates
inactive
Active G-Protein-GTP
-> allosteric modulator
of target effector
enzyme
active
18

19. •There are TWO broad subclasses of
trimeric G-protein-activated signal
transduction pathways:
depends on their target effector enzymes
A. adenylyl cyclase
B. phospholipase C
•All G-proteins – similar structure/activation
19

20. Activated G-protein-GTP activates Effector Enzyme
adenylyl cyclase that initiates the production of the 2nd
messenger cAMP
Activated
G-protein
20

21. cAMP
activates
target enzyme
Protein Kinase A (PKA)
phosphorylates
target proteins
Inactive
PKA
Active
PKA
21

22. inactive active
Phosphorylase kinase
Protein Kinase A (PKA)
Phosphorylates downstream target enzymes
Breaks down
Starch
into Glucose
22

23. cAMP regulated pathways
Function target tissue signal
Glycogen breakdown muscle,liver epinephrine
Heart rate cardiovascular epinephrine
Water reabsorption kidney antidiuretic
hormone
What are targets for Protein Kinase A??
23

24. How to shut it off?
Auto
Shut-off
G-protein -subunit is on a timer
Inherent
GTPase activity
No ligand
24

25. How to shut it off?
cAMP-
phosphodiesterase
rapidly cleaves
cAMP
(so short lived)
PDE
25

26. Caffeine, a stimulant found in coffee and
other beverages, inhibit PDE, causing
levels of cAMP to rise and increases heart
rate, wakefulness, and heightened
alertness
26

27. What if you can’t turn off cascade?
Vibrio cholera - causes cholera
Normal gut: H20, NaCl, NaHCO3 secretion
controlled by hormones via Gs/cAMP signal
pathways
V. cholera – secretes enterotoxin, chemically
modifies Gs – no GTPase activity - stays ON
Severe watery diarrhea – dehydration, death
27

28. VIDEO: SIGNAL TRANSDUCTION
28

29. TWO subclasses of trimeric G-protein-activated
signal transduction pathways:
A. target protein adenylate cyclase
cAMP-> PKA
B. target protein phospholipase C (PLC)
29

30. target effector enzyme
is Phospholipase C
PLC cleaves a membrane
phospholipid (Phoshatidyl
inositol) to
two 2nd Messengers:
InositolTrisphosphate
(IP3) &
Diacylglycerol (DAG)
30

31. DAG
Activates
Protein
Kinase C
(Starts
Cascade)
IP3
Ligand
for ER
ligand-
gated
Ca++
channels
 Ca++ levels
31

32. Protein Kinase C phosphorylates target proteins
(ser & thr)
- cell growth
- regulation of ion channels
- cytoskeleton
- increases cell pH
- protein secretion
Ca++
Binds & activates calmodulin => Calmodulin-binding
proteins activated => (kinases & phosphatases)
Response:
32

33. III. Receptors for Signal Molecules:
B- Membrane Receptors
33
It is a matter for drug development and drug discovery

34. III. Receptors for Signal Molecules:
B- Membrane Receptors
• Enzyme-linked receptors function both as
enzymes and as receptors
• Most enzyme-linked receptors are tyrosine
kinases, other are guanylate cyclases, which
catalyze the conversion of GTP to the second
messenger cGMP
e.g. Growth factor receptors
3-
Smooth muscle relaxation
nitroglycerine, Viagra “erection” (block cGMP breakdown) 34

35. III. Receptors for Signal Molecules: Summary
35

36. IV. Signaling proteins:
• Many signaling proteins act as molecular switches
• Two ways to activate/deactivate signaling proteins
36

37. IV. Signaling proteins:
• Signaling proteins
Kinases
Phosphatases
GTPases
Adapters
• Two main types of kinases
- tyrosine kinase
- serine/threonine kinase
• Two types of GTP-binding
proteins
- Trimeric G proteins
- Monomeric GTPases
37

38. V. Second Messenger System:
38

39. VI. Conclusions:
• Signaling is endocrine, paracrine, synaptic, or direct cell
contact
• Signal transduction is mediated by receptor proteins
• Receptors bind primary signal (ligand)
• Some amplification event occurs
- Example:
ligand gated ion channel opens
influx of ions triggers change in activity
(vesicle fusion in nerve end, contraction in39

40. VI. Conclusions:
- Example: ligand binds to 7-pass membrane receptor
catalyzes GTP exchange to Ga-subunit of trimeric G-
protein
active Ga-subunit-GTP is allosteric activator of effector
enzymes:
- ADENYLATE CYCLASE: makes cyclic AMP
- PHOSPHOLIPASE C: makes DAG and IP3
(these second messengers activate target enzymes that
trigger cascades)
- Must shut off cascade: removal of ligand, hydrolysis of GTP,
phosphodiesterase, protein phosphatases, Ca++ ion pumps
40

41. VII. Questions
41

42. 1. Which of the following best describes a signal transduction pathway?
a. Binding of a signal molecule to a cell protein
b. Catalysis mediated by an enzyme
c. Series of changes in a series of molecules resulting in a response
d. All of the above
2. Which of the following steps in an intracellular signaling pathway amplifies the
signal?
a. Synthesis of a secondary messenger
b. Activation of a protein kinase
c. Binding of ligand to receptor
d. a & b
42

43. 3. Regarding signal transduction process, which sequence is correct?
a. Transduction, reception and response
b. Reception, transduction and response
c. Response, transduction and reception
d. Reception, transduction, response and termination
4. Cellular surface receptors
a. Bind to hydrophobic signal molecules
b. Bind to hydrophilic signal molecules
c. Bind to both hydrophobic and hydrophilic signal molecules
d. None of the above
43

44. 5. In reactions mediated by protein kinases, what does phosphorylation of successive
proteins do to drive the reaction?
a. Make a functional ATP
b. Change a protein from its inactive to active form
c. Change a protein from its active to inactive form
d. All of the above
6. Which of the following is an example of signal amplification?
a. Catalysis of many cAMP molecules by several simultaneously binding signal molecules
b. Activation of 100 molecules by a single signal binding event
c. Activation of a specific gene by a growth factor
d. All of the above
44

45. 7. Effector (adenylyl cyclase)
a. Generates cAMP as a second messenger and activates PKA
b. Generates cAMP as a second messenger but does not activate PKA
c. Generates cGMP as a second messenger and activates PKA
d. a and c
8. Gs G proteins
a. Activate adenylyl clyclase
b. Inhibit adenylyl clyclase
c. Do not affect adenylyl clyclase
d. None of the above
45

46. 9. cAMP signaling pathway is terminated by
a. Inherent GTPase activity of G protein ἀ-subunit
b. Activation of the second messenger cAMP
c. Generation of AMP from cAMP by PDE
d. a and c
10. DAG
a. Activates PKA
b. Activates PKC
c. Inhibit both PKA & PKC
d. None of the above
46

47. 47