1. Molecular Biology of the Cell
Alberts • Johnson • Lewis • Raff • Roberts • Walter
Molecular Biology of the Cell
Fifth Edition
Chapter 15
Mechanisms of Cell Communication
Copyright © Garland Science 2008

2. Communication between cells is mediated by extracellular signals
Figure Molecular Biology of the Cell (© Garland Science 2008)

3. Cells respond to the extracellular environment: example: Saccharomyces cerevisiae
Figure Molecular Biology of the Cell (© Garland Science 2008)

4. Figure 15-3a Molecular Biology of the Cell (© Garland Science 2008)

5. Figure 15-3b Molecular Biology of the Cell (© Garland Science 2008)

6. Figure 15-4 Molecular Biology of the Cell (© Garland Science 2008)

7. - Act at very low concentration
Endocrine signaling :
- slow
- Act at very low concentration
Figure 15-5a Molecular Biology of the Cell (© Garland Science 2008)

8. - High local concentration
Synaptic signaling
- Fast and precise
- High local concentration
Figure 15-5b Molecular Biology of the Cell (© Garland Science 2008)

9. Extracellular signal can act slow or rapidly to change the behavior of a target cell
Figure Molecular Biology of the Cell (© Garland Science 2008)

10. Gap junctions allow neighboring cells to share signaling information
Allow small molecules to pass freely between cells, like Calcium, Cyclic AMP (2nd messenger)
Figure Molecular Biology of the Cell (© Garland Science 2008)

11. Cells are programmed to respond to specific combinations of extracellular signal molecules
Figure Molecular Biology of the Cell (© Garland Science 2008)

12. Different types of cells usually respond differently to the same extracellular signal molecules
Figure Molecular Biology of the Cell (© Garland Science 2008)

13. The fate of some developing cells depends on their position in Morphogen gradients
Figure Molecular Biology of the Cell (© Garland Science 2008)

14. The cell can alter the concentration of an intracellular molecule quickly if the lifetime of the molecule is short
Figure Molecular Biology of the Cell (© Garland Science 2008)

15. Nitric oxide acts as a signaling molecule, it relaxes smooth muscles
Nitroglycerides used on patients with angina – reduces the work load of the heart.
Figure 15-12b Molecular Biology of the Cell (© Garland Science 2008)

16. These bind to intracellular receptors to regulate gene expression
Small hydrophobic molecules that diffuse directly across the plasma membrane
These bind to intracellular receptors to regulate gene expression
Figure Molecular Biology of the Cell (© Garland Science 2008)

17. THE NUCLEAR RECEPTORS SUPERFAMILY
Steroid hormones (cortisol) made of cholesterol, cortisol is made in the adrenal cortex, influences metabolism.
Steroid sex hormones made by testes and ovaries – reponsible for secondary sex characteristics
Vitamin D – made in the skin, regulates calcium metabolism.
* The nuclear receptor (with ligand) then binds to DNA to regulate transcription
Figure 15-14a Molecular Biology of the Cell (© Garland Science 2008)

18. Ligand binding alters the conformation of the receptor
Figure 15-14b Molecular Biology of the Cell (© Garland Science 2008)

19. * In some cases ligand binding inhibits transcription
Ligand binding alters the conformation of the receptor: inhibitor dissociates and coactivator binds
* In some cases ligand binding inhibits transcription
Figure 15-14c Molecular Biology of the Cell (© Garland Science 2008)

20. The transcription response takes place in multiple steps: primary and secondary responses
Figure Molecular Biology of the Cell (© Garland Science 2008)

21. THE THREE LARGEST CLASS OF CELL-SURFACE RECEPTORS
Most extracellular signals do not enter the cell like the hydrophobic ones, but they bind to specific receptors at the plasma membrane
Ion-channel-coupled
G-protein-coupled
Enzyme-coupled
These receptors act as signal transducers

22. Mediated by neurotransmitters that open / close the channel
Involved in rapid synaptic signaling between nerve cells, and nerve and muscle cells
Mediated by neurotransmitters that open / close the channel
Most belong to a family of multipass transmembrane proteins
Figure 15-16a Molecular Biology of the Cell (© Garland Science 2008)

23. All belong to a family of multipass transmembrane proteins
A trimeric G protein (GTP binding) mediates the interaction between the activated receptor and this target protein.
All belong to a family of multipass transmembrane proteins
Figure 15-16b Molecular Biology of the Cell (© Garland Science 2008)

24. Function as enzymes or associate with enzymes that they activate.
Are usually single pass transmembrane proteins, ligand binding site outside the cell and catalytic (enzyme-binding) site inside the cell.
Majority are protein kinases or associate with protein kinases.
Figure 15-16c Molecular Biology of the Cell (© Garland Science 2008)

25. Most activated cell-surface receptors relay signals via small molecules and a network of intracellular signaling proteins: called second messengers
Examples of small messengers:
In cytosol:
Cyclic AMP : cAMP
Calcium ion
Fat soluble:
Diacylglycerol
Large intracellular signaling proteins
Figure Molecular Biology of the Cell (© Garland Science 2008)

26. Many intracellular signaling proteins function as switches that are activated by phosphorylation or GTP binding
Ser/thre kinases are majority
Tyrosine kinases
Figure Molecular Biology of the Cell (© Garland Science 2008)

27. Small monomeric GTPases regulated by GTP/GDP binding
Figure Molecular Biology of the Cell (© Garland Science 2008)

28. Signal integration: two pathways cause phosphorylation of one target at different sites
Figure Molecular Biology of the Cell (© Garland Science 2008)

29. TYPES OF INTRACELLULAR SIGNALING COMPLEXES
The scaffold holds signaling proteins in close proximity, the components can interact at high local concentration and be sequentially activated, efficiently and selectively
Figure 15-21a Molecular Biology of the Cell (© Garland Science 2008)

30. TYPES OF INTRACELLULAR SIGNALING COMPLEXES
Transient assembly of complexes, due to phosphorylation (that is reversible)
Figure 15-21b Molecular Biology of the Cell (© Garland Science 2008)

31. TYPES OF INTRACELLULAR SIGNALING COMPLEXES
Receptor activation leads to the production of modified phospholipids (phosphinositides), which recruit specific intracellular signaling proteins.
Figure 15-21c Molecular Biology of the Cell (© Garland Science 2008)

32. Induced proximity via interaction domains, used to relay signals from protein to protein
Figure Molecular Biology of the Cell (© Garland Science 2008)

33. When a cell responds to extracellular signals, it can be a smooth graded or a switch like response
Figure Molecular Biology of the Cell (© Garland Science 2008)

34. Looking at a whole population, the response may appear smooth while each cell is having an all or non response
It is important to look at individual cells to detect all-or-none responses
Figure 15-24b, c Molecular Biology of the Cell (© Garland Science 2008)

35. Example:
Adrenaline binding to a G-protein-coupled cell-surface receptor increases the intracellular concentration of cyclic AMP which in turn activates enzymes that promote glycogen breakdown and inhibit enzymes that promote glycogen synthesis.
Figure Molecular Biology of the Cell (© Garland Science 2008)

36. Intracellular signaling incorporate feedback loops
Figure Molecular Biology of the Cell (© Garland Science 2008)

37. Positive feedback mechanism giving switch-like behavior
Figure Molecular Biology of the Cell (© Garland Science 2008)

38. Positive feedback mechanism depends on the intensity of the stimulus, that results in a signal that persists
Negative feedback mechanism counteracts the effect of a stimulus making the system less sensitive
Figure Molecular Biology of the Cell (© Garland Science 2008)

39. Target cells can become adapted (desensitized) to an extracellular signal molecule
Figure Molecular Biology of the Cell (© Garland Science 2008)

40. More than 700 GPCRs in humans
G-protein coupled receptors, the largest class of cell surface receptors
More than 700 GPCRs in humans
Sigh, smell and taste use these receptors
One signal can activate many GPCRs
Figure Molecular Biology of the Cell (© Garland Science 2008)

41. Trimeric G-proteins relay signals from GPCRs
Various types of G-proteins, each one specific for a particular set of GPCRs, and particular set of target proteins in the membrane
They all have similar structures and operate similarly.
Gproteins have three subunits: alpha, beta and gamma.
Alpha-GDP unstimulated
Alpha-GTP stimulated (has intrinsic GTPase); also regulators of G-protein signaling act as GTPases
Figure Molecular Biology of the Cell (© Garland Science 2008)

42. Some G-proteins regulate the production of Cyclic AMP
Cyclic AMP acts as a second messenger
Figure Molecular Biology of the Cell (© Garland Science 2008)

43. Cyclic AMP is synthesized from ATP by a plasma membrane bound enzyme adenylyl cyclase and is quickly destroyed by cAMP phosphodiesterase
Different G-proteins cause different effect of cAMP:
Stimulatory G-protein (Gs) activates adenylyl cyclase
Inhibitory G-protein (Gi) inhibits adenylyl cyclase
Ex: cholera toxin is an enzyme that catalyzes transfer of ADP ribose from NAD+ to Gs. Now Gs can no longer hydrolyze the GTP and is always ON, making adenylyl cyclase active always, more cAMP causes more Cl- to be in the gut (and hence more water)
Figure Molecular Biology of the Cell (© Garland Science 2008)

44. Individuals with genetic defects in Gs alpha show decrease response to some hormones (so they have metabolic abnormalities, abnormal bone development and are mentally retarded).
Table Molecular Biology of the Cell (© Garland Science 2008)

45. Cyclic AMP dependent protein kinase (PKA) mediates most of the effects of cyclic AMP
PKA is a Ser/Thre Kinase
Figure Molecular Biology of the Cell (© Garland Science 2008)

46. A rise in cyclic AMP can alter gene transcription
Figure Molecular Biology of the Cell (© Garland Science 2008)

47. Many GPCRs exert their effects mainly via G proteins that activate the plasma membrane - bound enzyme phospholipase C-b (PLCb)
Table Molecular Biology of the Cell (© Garland Science 2008)

48. Phospholipase C-b (PLCb) works on PIP2 to make DAG and IP3
Figure Molecular Biology of the Cell (© Garland Science 2008)

49. IP3 diffuses in the cytoplasm and binds to the ER causing Calcium release in the cytosol
Figure Molecular Biology of the Cell (© Garland Science 2008)

50. Calcium functions as an intracellular mediator, for example during fertilization it initiates embryonic development
Figure Molecular Biology of the Cell (© Garland Science 2008)

51. In a resting cell, several mechanisms ensure that calcium concentration remains low
Figure 15-41a Molecular Biology of the Cell (© Garland Science 2008)

52. In a resting cell, several mechanisms ensure that calcium concentration remains low
Figure 15-41b Molecular Biology of the Cell (© Garland Science 2008)

53. Various Ca2+-binding proteins help to relay the cytosolic Ca2+ signal: Calmodulin, when bound to Calcium changes conformation
Figure Molecular Biology of the Cell (© Garland Science 2008)

54. Activated Calmodulin binds and activates other proteins: CAM Kinase
Figure Molecular Biology of the Cell (© Garland Science 2008)

55. Table 15-3 Molecular Biology of the Cell (© Garland Science 2008)

56. GPCR Kinases and arrestins in GPCR desesitization
Figure Molecular Biology of the Cell (© Garland Science 2008)

57. Receptor Tyrosine kinases
Figure Molecular Biology of the Cell (© Garland Science 2008)

58. Table 15-4 Molecular Biology of the Cell (© Garland Science 2008)

59. Figure 15-53a Molecular Biology of the Cell (© Garland Science 2008)

60. Figure 15-53b Molecular Biology of the Cell (© Garland Science 2008)

61. Figure 15-54 Molecular Biology of the Cell (© Garland Science 2008)

62. Figure 15-55a Molecular Biology of the Cell (© Garland Science 2008)

63. Table 15-5 Molecular Biology of the Cell (© Garland Science 2008)

64. Figure 15-66 Molecular Biology of the Cell (© Garland Science 2008)