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 Intracellular molecule biological effect Signal transduction

4. §1 Signaling Molecules

5. 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.

6. Extracellular molecules Intracellular molecules

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

8. (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

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

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

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

12. GAS MOLECULE

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

14. 2. Intracellular molecule Ca 2+ ions DG, ceramide lipid derivatives IP 3 carbohydrate derivatives cAMP cGMP nucleotides Ras, JAK, Raf proteins

15. 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 Ca 2+, DG, Cer, IP 3, cAMP, cGMP

16. 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.

17. Effect by membrane receptors Effect by intracellular receptors Intracellular molecules Extracellular molecules Signal molecules cAMP, cGMP, IP 3, DG, Ca 2+ Proteins and peptides: Hormones, cytokines Amino acid derivatives: Catecholamines Fatty acid derivatives: Prostaglandins Steroid hormones, Thyroxine, VD 3

18. §2 Receptor

19. 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

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

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

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

26. 1) 7-helices transmembrane receptor (2) G Protein-Coupled Receptors (serpentine R)

27. Cytosolic side Oligosaccharide unit

28. 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. 2) G protein (Guanylate binding protein)

30. G s →  s →AC→cAMP↑ G i →  i →AC→cAMP↓ G q →  q →PI-PLC→IP 3 +DAG G o →  o →ion channel G t →  t →cGMP PDE→cGMP→ Rhodopsin 3) Classes of G protein

32. Glucagon  -adrenaline →  s →AC↑ ACTH  -adrenaline angiotensin Ⅱ acetylcholine(M 2 M 4 ) GF release inhibitory factor →  i →AC↓

34. Ribosylation of Arg of G  G  s -ATPG  s -ADP AC cAMPCl - + H 2 O Cavity of intestine diarrhea HCO 3 - Cholera toxin ATPase

35. Pertussis toxin  i -ADP-ribosylation G i AC↑ allergy of histamine cAMP ↑

36. AC cGMP PDE (phosphodiesterase ） PLC PLA 2 Channel protein 4) Effect proteins of G protein

37. cAMP ATP

39. 5) Pathway of G protein linked receptor HRG protein Es secondary messeger Protein kinase Phophorylation of Es or functional protein Biological effect

40. (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

42. Tyrosine protein kinase Receptor or receptor tyrosine kinase (RTK) Cys-rich domain Immunoglobulin -like domain EGFRIGF-1RPDGFRFGFR

43. Intracellular insulin effects Cytosol Insulin

44. Non-receptor tyrosine kinase (NRTK)

45. Domain of Downstream molecules of TPKR SH 2 domain (Scr homology 2 domain) SH 3 domain PH domain (pleckstrin homology domain)

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