SIGNAL TRANSDUCTION

1. Cellular Signal Transduction M.Prasad Naidu MSc Medical Biochemistry, Ph.D.Research Scholar

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

4. 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.

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

6. (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

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

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

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

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

11. GAS MOLECULE

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

13. 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

14. 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.

15. 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

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

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

20. 1) 7-helices transmembrane receptor (2) G Protein-Coupled Receptors (serpentine R)

21. Oligosaccharide unit Cytosolic side

22. 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)

23. G protein Coupled Receptors • The human genome encodes more than 1000 Gprotein Coupled Receptors (GPCR), that transduce messages as diverse as light, smells, taste, and hormones • An example is the beta-adrenergic receptor, that mediates the effects of epinephrine on many tissues:…

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

30. Gsvs Givs Gq Gs and Gi coupled to adenylate cyclase  [cAMP] G q coupled to phospholipase C  [Ca2+]

31. Gsvs. Gi Regulation of Adenylate Cyclase Activity Gsstimulates adenylate cyclase Giinhibits adenylate cyclase e.g. epinephrine can increase or decrease intracellular cAMP concentrations, depending upon the receptor to which it binds adrenergic receptors couple to Gs, whereas 2adrenergic receptors couple to Gi

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

33. Inhibition of Gs and Gi by Bacterial Toxins Cholera toxin effects on Gs: ADP ribosylation of an Arg residue in the s subunit of Gs inhibition of associated GTPase activity Pertussis toxin effects on Gi: ADP ribosylation of a Cys residue in the i subunit of Gi  an inability to inhibit adenylate cyclase activity. Thus, both toxins cause increased intracellular cAMP concentrations! © 2000 by W. H. Freeman and Company. All rights reserved.

34. (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

37. Insulin Intracellular insulin effects Cytosol

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

39. 2. Intracellular receptor (transcription regulated receptor) Intracellular R is trans-acting element cis-acting element gene expression Localized in the cytosol and/or in the nucleus. ligand: Steroid H, Vit D3, Thyroxine

42. 4. Control of receptor activity Phosphorylation or dephosphorylation of R Phospholipid of membrane Enzyme catalyzed hydrolysis G protein regulation

43. 5.Function of receptor (1) Recognize the special ligand (2) Binding to special ligand (3) Signal transduction biological effect

44. Signal transduction mediated by membrane receptor cAMP dependent-protein kinase A pathway cGMP dependent PKG pathway Ca2+ dependent PK pathway Tyrosine protein Kinase pathway NF-κB pathway

45. 1. cAMP dependent-protein kinase A pathway H R G protein AC cAMP PKA Phosphorylation of Es or functional proteins Biological effects

46. (1) cAMP metabolism PDE AC PDE： Phosphodiesterase AC： Adenylate cyclase

49. (3) PKA effect

50. Phosphorylate specifically Ser/Thr residues in several proteins （1）Regulation of metabolism （2）Regulation of gene expression