Signal transmission and signal transduction

1. Signal transmission and signal transduction XIA Qiang, MD & PhD Department of Physiology Room 518, Block C, Research Building School of Medicine, Zijingang Campus Email: xiaqiang@zju.edu.cn Tel: 88206417 (Undergraduate school), 88208252 (Medical school)

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

11. Intercellular signal transmission • Electrical transmission Gap junction

12. Cardiac Muscle 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

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

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

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

16. Transmembrane signal transduction

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

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

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

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

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

22. Activation and Inactivation of the G Protein

23. G-protein-coupled Receptors

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

26. Main signaling pathways (1) cAMP-PKA pathway (2) IP3-Ca2+ pathway (3) DG-PKC pathway (4) G protein-ion channel pathway

27. 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) IP3-Ca2+ pathway: Gq (3) DG-PKC pathway: Gq DAG: diacylglycerol IP3: inositol 1,4,5-trisphosphate PIP2: phospholipid phosphatidylinositol 4,5-bisphosphate

33. This receptor-G-protein complex is linked to and activates phospholipase C, leading to an increase in IP3 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. Transmembrane signal transduction • Mediated by G protein-linked receptor • Mediated by enzyme-linked receptor • Mediated by ion channel

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 kinase • Ras: G protein. It consists of an a subunit, b subunit, and g subunit • MAPKKK: MAPK kinasekinase • MAPKK: MAPK kinase • MKP: MAPK phosphatases • TF: 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