Chapter 15 Cellular Signal Transduction

1. Chapter 15 Cellular Signal Transduction The biochemistry and molecular biology department of CMU

2. When environment changes: Monad——responds directly. Multicellular organisms——signal through elaborate system of intercellular or intracellular communication，and consequently regulate functions of organisms.

3. Signaling molecule Receptor of target cell Signal transduction Intracellular molecule biological effect

5. §1 Signaling Molecules

6. Signaling molecules • Signaling molecules, which are released by signal-producing cells, reach and transfer biological signals to their target cells to initiate specific cellular responses.

7. Extracellular molecules • Intracellular molecules

8. 1. Extracellular molecules protein & peptides: Hormone, cytokine AA & its derivatives: Gly, Glu, adrenaline, thyroxine Steroid: Sex Hormone, glucocorticosteroid Fatty acid derivatives: prostaglandin

9. (1) Paracrine signaling (local chemical mediators) • Secreted by common cells. • Reach neighboring target cells by passive diffusion. • Time of action is short. • Such as GF, PG

10. (2) Endocrine signal • Secreted by endocrine cells. • Reach target cells by blood circulation. • Time of action is long. • Such as insulin, thyroxine, adrenalin

11. (3) Synaptic signal (neurotransmitters) • Secreted by neuronal cells. • Reach another neuron by synaptic gap. • Time of action is short. • Such as Acetylcholine (Ach), noradrenaline

12. (4) Gaseous signal • Simple structure, half life is short and active in chemistry . • Such as NO, CO.

13. GAS MOLECULE

14. (5) Autocrine signal • Act back to their own cells. • Such as GF, cytokine, interferon, interleukin.

15. 2.Intracellular molecule • Ca2+ ions • DG, ceramide lipid derivatives • IP3 carbohydrate derivatives • cAMP cGMP nucleotides • Ras, JAK, Raf proteins

16. Second messenger: Small molecules synthesized in cells in response to an external signal are the second messengers, which are responsible for intracellular signal transduction. Such as Ca2+, DG, Cer, IP3,cAMP, cGMP

17. Third messengers: Third messengers are the molecules which transmit message from outside to inside of nucleous or from inside to outside of nucleous, also called DNA binding protein.

18. Proteins and peptides: Hormones, cytokines Effect by membrane receptors Amino acid derivatives: Catecholamines Fatty acid derivatives: Extracellular molecules Prostaglandins Effect by intracellular receptors Signal molecules Steroid hormones, Thyroxine, VD3 Intracellular molecules cAMP, cGMP, IP3, DG, Ca2+

19. §2 Receptor

20. Receptor Receptors are specific membrane proteins, which are able to recognize and bind to corresponding ligand molecules, become activated, and transduce signal to next signaling molecules. Glycoprotein or Lipoprotein

21. ligand A small molecule that binds specifically to a larger one; for example, a hormone is the ligand for its specific protein receptor.

22. Membrane receptors membrane Glycoprotein • Intracellular receptors Cytosol or nuclei DNA binding protein

23. 1. membrane receptors (1) Ligand-gate ion channels type (cyclic receptor) ligand→receptor→ion channel open or close

27. (2) G Protein-Coupled Receptors (serpentine R) 1) 7-helices transmembrane receptor

28. Oligosaccharide unit Cytosolic side

29. 2) G protein (Guanylate binding protein) G protein refers to any protein which binds to GDP or GTP and act as signal transduction. G proteins consist of three different subunits (, , -subunit). -subunit carries GTPase activity, binding and hydrolysis of GTP.

31. 3) Classes of G protein Gs→ s→AC→cAMP↑ Gi→ i→AC→cAMP↓ Gq→ q →PI-PLC→IP3+DAG Go→ o→ion channel Gt→ t→cGMP PDE→cGMP→ Rhodopsin

33. Glucagon -adrenaline →s →AC↑ ACTH -adrenaline angiotensin Ⅱ acetylcholine(M2 M4) GF release inhibitory factor →i→AC↓

35. Cholera toxin Ribosylation of Arg of G ATPase Gs-ATP Gs-ADP AC cAMP Cl- +H2O Cavity of intestine diarrhea HCO3-

36. Pertussistoxin i -ADP-ribosylation Gi AC↑ allergy of histamine cAMP ↑

37. 4) Effect proteins of G protein AC cGMP PDE (phosphodiesterase） PLC PLA2 Channel protein

38. cAMP ATP

40. 5) Pathway of G protein linked receptor H R G protein Es secondary messeger Protein kinase Phophorylation of Es or functional protein Biological effect

41. (3) Single transmembrane α-helix receptor • Tyrosine protein kinase Receptor (catalytic receptor) IGF－R, EGF－R • Non tyrosine protein kinase Receptor Growth Hormone R, interferon R

43. Cys-rich domain Immunoglobulin-like domain EGFR IGF-1R PDGFR FGFR Tyrosine protein kinase Receptor or receptor tyrosine kinase (RTK)

44. Insulin Intracellular insulin effects Cytosol

45. Non-receptor tyrosine kinase (NRTK)

46. Domain of Downstream molecules of TPKR SH2 domain (Scr homology 2 domain) SH3domain PH domain (pleckstrin homology domain)

48. (4) Guanylate cyclase (GC) receptor Membrane receptor –ANP Soluble receptor –NO, CO

50. 2. Intracellular receptor (transcription regulated receptor) Intracellular R is trans-acting elememt cis-acting element gene expression Localized in the cytosol and/or in the nucleus. ligand: Steroid H, VD3, Thyroxine