Signal transduction

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Signal transduction

  1. 1. Cellular Signal Transduction M.Prasad Naidu MSc Medical Biochemistry, Ph.D.Research Scholar
  2. 2. Monad——responds directly. Multicellular organisms——signal through elaborate system of intercellular or intracellular communication,and consequently regulate functions of organisms.
  3. 3. Signaling molecule Receptor of target cell Intracellular molecule biological effect Signal transduction
  4. 4. • Signaling molecules, which are released by signal-producing cells, reach and transfer biological signals to their target cells to initiate specific cellular responses.
  5. 5. protein & peptides: Hormone, cytokine AA & its derivatives: Gly, Glu, adrenaline, thyro xine Steroid: Sex Hormone, glucocorticosteroid Fatty acid derivatives: prostaglandin
  6. 6. • Secreted by common cells. • Reach neighboring target cells by passive diffusion. • Time of action is short. • Such as GF, PG
  7. 7. • Secreted by endocrine cells. • Reach target cells by blood circulation. • Time of action is long. • Such as insulin, thyroxine, adrenalin
  8. 8. • Secreted by neuronal cells. • Reach another neuron by synaptic gap. • Time of action is short. • Such as Acetylcholine (Ach), noradrenaline
  9. 9. • Simple structure, half life is short and active in chemistry . • Such as NO, CO.
  10. 10. • Act back to their own cells. • Such as GF, cytokine, interferon, interleukin.
  11. 11. GAS MOLECULE
  12. 12. • Ca2+ ions • DG, ceramide lipid derivatives • IP3 carbohydrate derivatives • cAMP cGMP nucleotides • Ras, JAK, Raf proteins
  13. 13. 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. 14. 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. 15. 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. 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. 17. (1) Ligand-gate ion channels type (cyclic receptor) ligand→receptor→ion channel open or close
  18. 18. 1) 7-helices transmembrane receptor
  19. 19. Cytosolic side Oligosaccharide unit
  20. 20. • 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.
  21. 21. 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:…
  22. 22. Gs→ s→AC→cAMP↑ Gi→ i→AC→cAMP↓ Gq→ q →PI-PLC→IP3+DAG Go→ o→ion channel Gt→ t →cGMP PDE→cGMP→ Rhodopsin
  23. 23. Gs vs Gi vs Gq Gs and Gi coupled to adenylate cyclase   [cAMP] G q coupled to phospholipase C   [Ca2+]
  24. 24. Gs vs. Gi Regulation of Adenylate Cyclase Activity Gs stimulates adenylate cyclase Gi inhibits 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 2 adrenergic receptors couple to Gi
  25. 25. Glucagon -adrenaline →s →AC↑ ACTH -adrenaline angiotensin Ⅱ acetylcholine(M2 M4) GF release inhibitory factor →i→AC↓
  26. 26. 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.
  27. 27. • Tyrosine protein kinase Receptor (catalytic receptor) IGF-R, EGF-R • Non tyrosine protein kinase Receptor Growth Hormone R, interferon R
  28. 28. Intracellular insulin effectsCytosol Insulin
  29. 29. Membrane receptor –ANP Soluble receptor – NO, CO (4) Guanylate cyclase (GC) receptor
  30. 30. 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
  31. 31. • Phosphorylation or dephosphorylation of R • Phospholipid of membrane • Enzyme catalyzed hydrolysis • G protein regulation
  32. 32. (1) Recognize the special ligand (2) Binding to special ligand (3) Signal transduction biological effect
  33. 33. • cAMP dependent-protein kinase A pathway • cGMP dependent PKG pathway • Ca2+ dependent PK pathway • • Tyrosine protein Kinase pathway • NF-κB pathway
  34. 34. H R G protein Phosphorylation of Es or functional proteins Biological effects PKA cAMPAC
  35. 35. ATP Mg2+ PPi cAMP H2O Mg2+ 5'-AMP AC PDE AC: Adenylate cyclase PDE: Phosphodiesterase
  36. 36. PDE H2O N N N N NH2 O H OHOH CH2 H H H OPO O O PO O O P O O O ATP ACPPi N N N N NH2 O H OHO CH2 H H H O PO O cAMP N N N N NH2 O H OHOH CH2 H H H OPO O O 5'-AMP
  37. 37. (3) PKA effect
  38. 38. Phosphorylate specifically Ser/Thr residues in several proteins (1)Regulation of metabolism (2)Regulation of gene expression
  39. 39. hormons: glucagon, epinephrine inactive ACactive AC ATP cAMP inactive PKA active PKA phosphorylase b kinase phosphorylase b kinase P ATP ADP H2O Pi phosphorylase b P P ATP ADP Pi H2O ATP ADP glycogen synthase glycogen synthase P H2OPi protein phosphatase-1 (active) (inactive) inhibitor-1 (active) inhibitor-1 (inactive) phosphorylase a ATP
  40. 40. (1) Ca2+ -DAG -dependent PKC pathway H R PIP2 G protein PLC IP3 DG ER PKC Ca2+ Biological effects Phosphorylation of Es or functional proteins
  41. 41. IP3 + R→open of Ca2+ channel →[Ca2+]↑ from ER [Ca 2+]i 0.01-1 mol/L(10-7 mol/L ) [Ca 2+]o 2.5mmol/L(10-3 mol/L ) 5000~10000× Ca2+ DG PKC ↑
  42. 42. • regulation of metabolism PKC →Ser/Thr-P of R, enzyme, Protein of Mb. • Gene expression
  43. 43. H R G protein PLC IP3 Ca2+ CaM CaMK Biological effects Phosphorylation of Es or functional proteins
  44. 44. Ca2+ binding protein 4 Ca2++ CaM → Ca2+- CaM ↓ CaM kinase↑ ↓ Ser/Thr - P ↓ Ca2+ pump, AC ↑ GC ↑ Es (glycogen synthase, phosphorylase kinase)
  45. 45. Biological effects Phosphorylation of Es or functional proteins ANP NO, CO Soluble GC PKG cGMP Receptor- linked GC
  46. 46. (2) Function of PKG Ser/Thr- P of protein and E Mg2+ PPi H2O Mg2+ GTP cGMP 5'-GMP GC PDE GC: Guanylate cyclase
  47. 47. ANP(atrial natriuretic peptides) ↓ GC NO ↓ cGMP ↓ PKG ↓ Vascular dilatation
  48. 48. cis-actingelement nucleus expression cell memberane phosphorylationof enzymes or proteins effects CaM-PK Ca2+ -CaMCa2+ IP3 DGcAMP cGMP PKA PKG PKC ATP GTP PIP2(PC) GAC GC GPL peptide hormones neurotransmitters AFP neurotransmitters hypothalamic pituitrin Ptrans-actingfactor
  49. 49. • TPK receptor is related to proliferation, differentiation, dissociation, carcinomatous change. • TPK: receptor TPK:Membrane. non receptor TPK:cytosol
  50. 50. • GRB2, SOS, Ras, Raf • Small G protein: Ras • MAPK (mitogen-activated protein kinase): MAPK、MAPKK、MAPKKK  • MAPKs belong to a family of serine/threonine kinases (kinases add  phosphate groups to/phosphorylate other proteins)  • They participate in cell growth, differentiation, transformation,  apoptosis (controlled cell death) and others
  51. 51. ÊÜÌåÐÍTPK ϸ °û Ä EGF, PDGF receptor TPK Ras-GTP SOS-P GRB2-P Raf-P MAPKK-P MAPK-P trans-acting factor expression nucleus -P
  52. 52.  (2) JAKs-STAT pathway • JAKs(JANUS KINASES) • STAT: Signal transductors and activator of transcription
  53. 53. ÖÊĤ ¸ÉÈÅËØÓ¦´ðÔª¼þ ºËĤ »ùÒò £- PP£- JAK 113 91 84 48 113 P 91P 84 P 48 113 91 84P P P interferons & GH inactive STAT Plasma membrane STAT complex Nuclear membrane gene Interferons response element transcription
  54. 54. • Steroid H, VD3, Thyroxine • Cytosolic R: glycocorticosteroid H • Nuclear R: thyroxine, estrogen, androgen, progesterone
  55. 55. Effect by membrane receptors Effect by intracellular receptors Intracellular molecules Extracellular molecules Signal molecules cAMP, cGMP, IP3, DG, Ca2+ Proteins and peptides: Hormones, cytokines Amino acid derivatives: Catecholamines Fatty acid derivatives: Prostaglandins Steroid hormones, Thyroxine, VD3

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