1. Signal transmission and signal transduction Xia Qiang, PhD Department of Physiology Rm C518, Block C, Research Building, School of Medicine Tel: 88208252 Email: xiaqiang@zju.edu.cn

2. OUTLINE  Intercellular signal transmission  Chemical transmission  Electrical transmission  Signal transduction pathway  Pathways initiated by intracellular receptors  Pathways initiated by plasma membrane receptors

3. Intercellular signal transmission  Chemical transmission  Chemical signals  Neurotransmitters:

4. Intercellular signal transmission  Chemical transmission  Chemical signals  Neurotransmitters:  Humoral factors:  Hormones  Cytokines  Bioactivators

5. Intercellular signal transmission  Chemical transmission  Chemical signals  Neurotransmitters:  Humoral factors:  Gas: NO, CO, etc.

6. Intercellular signal transmission  Chemical transmission  Chemical signals  Receptors  Membrane receptors  Intracellular receptors

7. Receptors on the surface of a cell are typically proteins that span the membrane

8. Cells B & C lack the matching receptors Therefore are not directly affected by the signal Only Cell A has the matching receptors for this chemical messenger, so it is the only one that responds

11. Intercellular signal transmission  Electrical transmission Gap junction

12. Low Magnification View The intercalated disk is made of several types of intercellular junctions. The gap junction provides a low resistance pathway for the action potential to spread from cell to cell Cardiac Muscle

13. Signal transduction pathway  Pathways initiated by intracellular receptors  Pathways initiated by plasma membrane receptors

14. … but at the target cell the signal moves easily through the membrane and binds to its receptor This hydrophobic signal requires a carrier protein while in the plasma …

15. Signal transduction pathway  Pathways initiated by intracellular receptors  Pathways initiated by plasma membrane receptors (transmembrane signal transduction)

16. Transmembrane signal transduction

17.  Mediated by G protein-linked receptor  Mediated by enzyme-linked receptor  Mediated by ion channel Transmembrane signal transduction

18. Binding of ligands to membrane-spanning receptors activates diverse response mechanisms

19.  Mediated by G protein-linked receptor  Mediated by enzyme-linked receptor  Mediated by ion channel Transmembrane signal transduction

20. The Nobel Prize in Physiology or Medicine 1994  "G-proteins and the role of these proteins in signal transduction in cells" Alfred G. GilmanMartin Rodbell

21. The Discovery of G Proteins Normal Lymphoma CellMutated Lymphoma Cell

22. Activation and Inactivation of the G Protein 1. The G protein, composed of alpha-, beta- and gamma-subunits, in its resting state with bound GDP. 2. The receptor with bound hormone activates the G protein and replaces GDP... 3....with GTP and the G proteins is activated. The subunits separate. 4. Some seconds later the GTP, bound to the alpha-subunit, is hydrolysed to GDP. The subunits recombine.

23. G-protein-coupled Receptors

24. Signaling molecules involved Second messenger G protein effector Protein kinase   

26. (1) cAMP-PKA pathway (2) IP 3 -Ca 2+ pathway (3) DG-PKC pathway (4) G protein-ion channel pathway Main signaling pathways

27. (1)cAMP-PKA pathway Gs, Gi

28. The cyclic AMP second messenger system

29. Adenylyl cyclase forms cAMP, a “second messenger” that activates enzymes used in cellular responses The phosphodiesterase enzymes “terminate” the second messenger cAMP

30. The cAMP system rapidly amplifies the response capacity of cells: here, one “first messenger” led to the formation of one million product molecules

31. Cells can respond via the cAMP pathways using a diversity of cAMP-dependent enzymes, channels, organelles, contractile filaments, ion pumps, and changes in gene expression

32. (2) IP 3 -Ca 2+ pathway: Gq (3) DG-PKC pathway: Gq

33. This receptor-G-protein complex is linked to and activates phospholipase C, leading to an increase in IP 3 and DAG, which work together to activate enzymes and to increase intracellular calcium levels

34. Click here to play the Membrane Bound Receptors, G Proteins, and Calcium Channels Flash Animation

35. (4) G protein-ion channel pathway

36. Binding of the ligand to the receptor alters the receptor’s shape, which activates an associated G-protein, which then activates effector proteins, i.e., enzyme functions or ion channels

39. The calcium-calmodulin system is similar to some of the cAMP pathways, because it results in the activation of protein kinases that can phosphorylate key proteins required for cellular responses

40. The “arachidonic acid cascade” is activated in inflammation responses; “cox inhibitors” block cyclooxygenase

41. Not all responses to hydrophilic signals are immediate: Increases in gene expression can occur, and the resulting proteins can increase the target cells’ response

42. Eicosanoid: A lipid mediator of inflammation derived from the 20-carbon atom arachidonic acid (20 in Greek is "eicosa") or a similar fatty acid. The eicosanoids include the prostaglandins, prostacyclin, thromboxane, and leukotrienes.

43.  Mediated by G protein-linked receptor  Mediated by enzyme-linked receptor  Mediated by ion channel Transmembrane signal transduction

44. Binding of the ligand to the receptor alters the receptor’s shape, which activates its enzyme function, phosphorylating an intracellular protein

45. (1) Tyrosine Kinase Receptor

46. Insulin receptor

47. Growth factor receptor

48. Mitogen-activated protein kinase (MAPK) pathway PTK: protein tyrosine kinasePTK: protein tyrosine kinase Ras: G protein. It consists of an  subunit,  subunit, and  subunitRas: G protein. It consists of an  subunit,  subunit, and  subunit MAPKKK: MAPK kinase kinaseMAPKKK: MAPK kinase kinase MAPKK: MAPK kinaseMAPKK: MAPK kinase MKP: MAPK phosphatasesMKP: MAPK phosphatases TF: tissue factorTF: tissue factor

49. (2) Receptor-associated tyrosine kinase JAK stands for Janus kinase or Just Another Kinase JAK2=Tyrosine protein kinase 2

50. Binding of the ligand to the receptor alters the receptor’s shape, which activates an associated enzyme function, phosphorylating an intracellular protein

51. (3) Receptor guanylyl cyclase Soluble GC

52.  Mediated by G protein-linked receptor  Mediated by enzyme-linked receptor  Mediated by ion channel Transmembrane signal transduction

53. Binding of the ligand to the receptor alters the receptor’s shape, which then opens (or closes) an ion channel

54. N 2 -ACh receptor channel

56. Any other pathway else? ? ?

57. Pheromone  Pheromones are chemicals emitted by living organisms to send messages to individuals of the same species.

58. The male silk moth bombyx mori (Fig. 1, left) can detect very low quantities of the sex pheromone bombykol emitted by the female, and at the same time distinguishes bombykol from many other, often similar, volatile compounds in the air. A first step of olfaction is the tranfer of bombykol to the pheromone receptor at the neuronal membrane via the pheromone-binding protein (BmorPBP). Highly efficient uptake and release kinetics of bombykol at the pheromone binding protein is essential for olfactory function. However, BmorPBP features a central hydrophobic binding cavity for bombykol, completely encapsulating the ligand (Fig. 1, right) and the exit/entrance gate for bombykol is not known. Yet, the ligand has to enter and exit the cavity fast and reversibly.

59. Activation of a receptor by a chemical messenger a. occurs when the messenger binds to the ligand-binding site of the receptor. b. is the first step leading to the ultimate response of a cell to the messenger. c. requires a change in receptor conformation. d. Both occurs when the messenger binds to the ligand- binding site of the receptor and is the first step leading to the ultimate response of a cell to the messenger are correct. e. All of the choices are correct. QUIZ

60. Activation of a receptor by a chemical messenger a. occurs when the messenger binds to the ligand-binding site of the receptor. b. is the first step leading to the ultimate response of a cell to the messenger. c. requires a change in receptor conformation. d. Both occurs when the messenger binds to the ligand- binding site of the receptor and is the first step leading to the ultimate response of a cell to the messenger are correct. e. All of the choices are correct. QUIZ

61. Epinephrine activates the cyclic AMP pathway in liver cells. Therefore, epinephrine a. probably binds a specific transmembrane receptor in these cells. b. elicits its response in liver cells through second messengers. c. probably binds a receptor in the nucleus of liver cells. d. Both probably binds a specific transmembrane receptor in these cells and elicits its response in liver cells through second messengers are correct. e. Both elicits its response in liver cells through second messengers and probably binds a receptor in the nucleus of liver cells are correct. QUIZ

62. Epinephrine activates the cyclic AMP pathway in liver cells. Therefore, epinephrine a. probably binds a specific transmembrane receptor in these cells. b. elicits its response in liver cells through second messengers. c. probably binds a receptor in the nucleus of liver cells. d. Both probably binds a specific transmembrane receptor in these cells and elicits its response in liver cells through second messengers are correct. e. Both elicits its response in liver cells through second messengers and probably binds a receptor in the nucleus of liver cells are correct. QUIZ

63. Second messengers a. are necessary for all receptor signal- transduction mechanisms. b. act in the cell cytoplasm. c. act as intercellular messengers. d. always function to activate enzymes. e. are always proteins. QUIZ

64. Second messengers a. are necessary for all receptor signal- transduction mechanisms. b. act in the cell cytoplasm. c. act as intercellular messengers. d. always function to activate enzymes. e. are always proteins. QUIZ

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