1. Last lecture:
reversible phosphorylation
regulation of transcription
This lecture:
signal transduction

2. Fridays MC H313
Biological Sciences Seminar Series
This Friday (19th):
The smallest hormone: birth, life and many deaths of nitric oxide

3. Intracellular signal transduction:
receptors or sensors
second messengers
kinases, phosphatases, transcription factors
downstream targets (proteins)

4. Intracellular Signal Transduction
Hormone receptors within the cell

5. Intracellular receptors:
- cytosolic
- nuclear

6. T4 T3

7. Intracellular Signal Transduction
Hormone receptors within the cell
Hormone receptors on cell membrane (facing external environment)

8. 2. Membrane receptors:
- laterally mobile
- interact with other membrane proteins
- catalytic

9. Intracellular Signal Transduction
Hormone receptors within the cell
Hormone receptors on cell membrane (facing external environment)
Signaling of entirely intracellular events

10. 3. Detection & signaling of entirely intracellular events

11. ATP synthetic processes
ATP ADP AMP
↑work → ↑[AMP]
AMP kinase
ATP synthetic processes

12. Intracellular Signal Transduction
Hormone receptors within the cell
Hormone receptors on cell membrane (facing external environment)
Signaling of entirely intracellular events

13. Roles of signal transduction?

14. Roles of signal transduction
(1) Permit adaptation
(2) Regulate response
(3) Coordinate related events

15. Features of signal transduction
2. Amplification
3. Diversification
4. Transience

16. Features of signal transduction
1. Transduction - conversion of one form to another
2. Amplification
3. Diversification
4. Transience

17. Features of signal transduction
1. Transduction - conversion of one form to another
2. Amplification - one receptor/binding event can affect big changes
3. Diversification
4. Transience

18. Features of signal transduction
1. Transduction - conversion of one form to another
2. Amplification - one receptor/binding event can affect big changes
3. Diversification - may affect related but different targets
4. Transience -

19. Features of signal transduction
1. Transduction - conversion of one form to another
2. Amplification - one receptor/binding event can affect big changes
3. Diversification - may affect related but different targets
4. Transience - can be turned off

20. An example of signal transduction: Receptors & G-proteins

22. G-protein activated by binding GTP

24. 1. Receptors that activate G-proteins
Largest family of receptors on cell surface (>1000 members)
Egs. epinephrine (adrenergic) receptor
Heterotrimers (one each of α, β, γ subunits)
Interact with a variety of effector molecules
Depend on lateral mobility of proteins in membrane

25. Eg. G-protein acting via adenylyl cyclase (AC)

26. In the cytosol:

27. Mobilization of glucose subunits from glycogen:
Hormone + receptor
→ G-protein
→ adenylyl cyclase
→ cAMP↑
→ PKA
→ phosphoprotein kinase
→ glycogen phosphorylase

28. G-proteins associated with phospholipase C and protein kinase C

30. G-proteins can:
Be stimulatory or inhibitory (eg. differential response to epinephrine)
Have different actions; depends on:
- particular combination of subunits (16 possible α isoforms; 5β; 11γ )
- presence of effectors nearby (egs. AC, phosphodiesterase, phospholipase)
Affect changes in cAMP, Ca2+, diacylglycerol

31. Receptors that are enzymes
Tyrosine kinases
Guanylyl cyclases
Catalyze cleavage (proteolysis) reactions (these may release an active transcription factor)

33. Example 1: the insulin receptor
Heterotetramer (2α and 2β subunits)
β subunit is tyrosine kinase (autophosphorylates tyrosines on receptor, then on other proteins)
Active IR stimulates PI 3-kinase activity
GLUT4 protein recruited to membrane from intracellular vesicles

36. Example 2: Nitric oxide receptor
Has guanylyl cyclase activity: GTP → cGMP

37. Protein regulation and signal transduction - summary and overview
Many strategies for altering specific and cellular activities
Fast vs slow responses
Specific activity vs amount of a protein
Protein kinases/phosphatases
Many transcription factors and HREs
Receptors: membrane, cytosol, nucleus
Receptor – effector mechanisms
Second messengers: signal amplification and/or diversification (egs. Ca++, cAMP, cGMP)

38. Read chapter 3 for Thursday