Third messanger

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  • 图 16-3 含 TPK 结 构 域 的 受 体
  • Third messanger

    1. 1. Chapter 15Cellular Signal Transduction The biochemistry and molecular biology department of CMU
    2. 2. When environment changes: Monad——responds directly. Multicellular organisms——signalthrough elaborate system ofintercellular or intracellularcommunication , and consequentlyregulate functions of organisms.
    3. 3. Signaling moleculeReceptor of target cell Signal transductionIntracellular molecule biological effect
    4. 4. §1 Signaling Molecules
    5. 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. 6. • Extracellular molecules• Intracellular molecules
    7. 7. 1. Extracellular moleculesprotein & peptides: Hormone, cytokineAA & its derivatives: Gly, Glu, adrenaline, thyroxineSteroid: Sex Hormone, glucocorticosteroidFatty acid derivatives: prostaglandin
    8. 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. 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. 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. 11. (4) Gaseous signal• Simple structure, half life is short and active in chemistry .• Such as NO, CO.
    12. 12.      GAS MOLECULE
    13. 13. (5) Autocrine signal• Act back to their own cells.• Such as GF, cytokine, interferon, interleukin.
    14. 14. 2. Intracellular molecule• Ca2+ ions• DG, ceramide lipid derivatives• IP3 carbohydrate derivatives• cAMP cGMP nucleotides• Ras, JAK, Raf proteins
    15. 15. Second messenger: Small molecules synthesized in cellsin response to an external signal arethe second messengers, which areresponsible for intracellular signaltransduction. Such as Ca2+, DG, Cer, IP3, cAMP,cGMP
    16. 16. Third messengers: Third messengers are the moleculeswhich transmit message from outsideto inside of nucleous or from inside tooutside of nucleous, also called DNAbinding protein.
    17. 17. Proteins and peptides: Effect by Hormones, cytokines membrane Amino acid derivatives: receptors Catecholamines Extracellular Fatty acid derivatives: molecules Prostaglandins Effect by Signal intracellular Steroid hormones,molecules Thyroxine, VD3 receptors Intracellular cAMP, cGMP, IP3, DG, Ca2+ molecules
    18. 18. §2 Receptor
    19. 19. Receptor Receptors are specific membraneproteins, which are able to recognizeand bind to corresponding ligandmolecules, become activated, andtransduce signal to next signalingmolecules. Glycoprotein or Lipoprotein
    20. 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. 21. • Membrane receptors membrane Glycoprotein• Intracellular receptors Cytosol or nuclei DNA binding protein
    22. 22. 1. membrane receptors(1) Ligand-gate ion channels type (cyclic receptor) ligand→receptor→ion channel open orclose
    23. 23. (2) G Protein-Coupled Receptors (serpentine R)1) 7-helices transmembranereceptor
    24. 24. Oligosaccharide unitCytosolic side
    25. 25. 2) G protein (Guanylate binding protein)• G protein refers to any protein whichbinds to GDP or GTP and act as signaltransduction.• G proteins consist of three differentsubunits (α, β, γ -subunit).• α -subunit carries GTPase activity,binding and hydrolysis of GTP.
    26. 26. 3) Classes of G protein Gs→ α s→AC→cAMP↑  Gi→ α i→AC→cAMP↓  Gq→ α q →PI-PLC→IP3+DAG  Go→ α o→ion channel Gt→ α t →cGMP PDE→cGMP→ Rhodopsin
    27. 27. Glucagonβ-adrenaline →α s →AC↑ACTHα-adrenalineangiotensin Ⅱ →α i→AC↓acetylcholine(M2 M4)GF release inhibitory factor
    28. 28.  
    29. 29. Cholera toxinRibosylation of Arg of Gα ATPaseG α s -ATP Gα s -ADP ACcAMP Cl- + H2O Cavity of intestine HCO3- diarrhea
    30. 30. Pertussis toxinα i -ADP-ribosylation Gi AC↑ cAMP ↑allergy of histamine
    31. 31. 4) Effect proteins of G protein AC cGMP PDE (phosphodiesterase ) PLC PLA2 Channel protein
    32. 32. cAMPATP
    33. 33. 5) Pathway of G protein linked receptor H R G protein Es secondary messeger Protein kinasePhophorylation of Es or functional protein Biological effect
    34. 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
    35. 35. Tyrosine protein kinase Receptor or receptor tyrosine kinase (RTK) Cys-rich domain Immunoglobulin -like domainEGFR IGF-1R PDGFR FGFR
    36. 36. Insulin IntracellularCytosol insulin effects
    37. 37. Non-receptor tyrosine kinase (NRTK)
    38. 38. Domain of Downstream molecules of TPKRSH2 domain (Scr homology 2 domain)SH3 domainPH domain (pleckstrin homology domain)
    39. 39. (4) Guanylate cyclase (GC) receptorMembrane receptor –ANPSoluble receptor – NO, CO
    40. 40. 2. Intracellular receptor (transcription regulated receptor) Intracellular R is trans-actingelememt cis-acting elementgene expression Localized in the cytosol and/or inthe nucleus. ligand: Steroid H, VD3, Thyroxine
    41. 41. 3. Properties of binding of H and R• highly specificity• highly affinity• saturation• reversible binding• special function model
    42. 42. 4. Control of receptor activity• Phosphorylation or dephosphorylation of R• Phospholipid of membrane• Enzyme catalyzed hydrolysis• G protein regulation
    43. 43. 5. Function of receptor(1) Recognize the special ligand(2) Binding to special ligand(3) Signal transduction biological effect
    44. 44. §3 Pathway of Signal Transduction
    45. 45. 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  • TGF- βpathway
    46. 46. 1. cAMP dependent-protein kinase A pathway H R G protein AC cAMP PKAPhosphorylation of Es or functional proteins Biological effects
    47. 47. (1) cAMP metabolism AC PDEATP 2+ cAMP 2+ 5-AMP Mg Mg PPi H2OPDE : PhosphodiesteraseAC : Adenylate cyclase
    48. 48. NH2 N N O O O N NO P O P O P O CH2 O ATP O O O H H H H OH OH PPi AC NH2 NH2 N N N N N N O N N PDE O CH2 O O P O CH2 O 5-AMP cAMP H H H2O O H H H H H H O P O OH OH OH O
    49. 49. (2) Mechanism of cAMP effect Activate cAMP-dependentprotein kinase (PKA).
    50. 50. (3) PKA effect
    51. 51. Phosphorylate specifically Ser/Thr residues in severalproteins ( 1 ) Regulation ofmetabolism ( 2 ) Regulation of geneexpression
    52. 52. hormons: glucagon, epinephrine active AC inactive AC ATP phosphorylase b kinase PiATP cAMPinactive PKA active PKA P ADP phosphorylase b kinase H2O ATP ADP ATP ADP P Pglycogen glycogensynthase phosphorylase b phosphorylase a synthase(active) (inactive) Pi H2O Pi H2O protein phosphatase-1 inhibitor-1 inhibitor-1 P (inactive) ATP (active)
    53. 53. CRE : cAMP response element (TGACGTCA)CREB: CRE binding protein
    54. 54. CRE DNA Transcription mRNA CREB CREB CR CR CRE EB EB CRCREB PP B CREB P EB P P P PKA PKA P P
    55. 55. 2. Ca2+ dependent PK pathway (1) Ca2+ -DAG -dependent PKC pathway PIP2H R G protein PLC IP3 DG ER Ca2+ PS PKC Phosphorylation of Es or functional proteins Biological effects
    56. 56. [Ca 2+]i 0.01-1 µmol/L ( 10-7 mol/L )[Ca 2+]o 2.5mmol/L ( 10-3 mol/L )5000~10000×
    57. 57. 1 ) Function of DG and IP3 IP3 + R→open of Ca2 +channel →[Ca2 + ]↑ DG PKC ↑ PS, Ca2 +
    58. 58. 2 ) Function of PKC• regulation of metabolism PKC →Ser/Thr-P of R, enzyme, Protein of Mb.• Gene expression  
    59. 59. Early response: PKC Trans-acting factor-PImmediate early genes Third messenger Late response: PKC Third messenger-P Activate genes Cell proliferation
    60. 60. (2) Ca2 + -CaM dependent proteinkinase pathwayH R G protein PLC IP3 Ca2+ CaM CaMK Phosphorylation of Es or functional proteins Biological effects
    61. 61. Calmodulin (CaM ): Ca2 + binding protein 4 Ca2 + + CaM → Ca2 + - CaM ↓ CaM kinase↑ ↓   Ser/Thr-P ↓ Ca2 + pump, AC ↑ GC ↑Es (glycogen synthase, phosphorylasekinase)
    62. 62. 3. cGMP-dependent PKG pathway ANP NO, CO Receptor- linked GC cGMP Soluble GC PKGPhosphorylation of Es or functional proteins Biological effects
    63. 63. (1) cGMP GC PDEGTP 2+ cGMP 2+ 5-GMP Mg Mg PPi H2O GC: Guanylate cyclase (2) Function of PKG Ser/Thr- P of protein and E
    64. 64. ANP ( atrial natriureticpeptides ) ↓ GC NO ↓ cGMP ↓ PKG ↓Vascular dilatation
    65. 65. peptide hormones neurotransmittersneurotransmitters AFP hypothalamic pituitrin G AC GC G PL cell memberane ATP GTP PIP2(PC) cAMP cGMP IP3 DG Ca2+ Ca2+-CaM PKA PKG PKC CaM-PK phosphorylation of enzymes or proteins effects trans-acting factor P cis-acting element nucleus expression
    66. 66. 4. Tyrosine-protein kinase pathway (TPK)• TPK receptor is related to proliferation, differentiation, dissociation, carcinomatous change.• TPK : receptor TPK : Mb. non receptor TPK : cytosol
    67. 67. (1) Receptor TPK - Ras - MAPK pathway• GRB2, SOS, Ras, Raf• Small G protein: Ras• MAPK (mitogen-activated protein kinase) : MAPK 、 MAPKK 、 MAPKKK
    68. 68. EGF, PDGF GRB2 - P ϸreceptor TPK ÊÜ ÐÍTPK Ìå Ras - GTP °û SOS - P Ĥ Raf - P MAPKK - P nucleus trans-acting factor - P MAPK - P expression
    69. 69. (2) JAKs - STAT pathway ligand non TPK receptor JAKs STAT gene expression
    70. 70. • JAKs• STAT: Signal transductors and activator of transcription
    71. 71. interferons Plasma membrane ÖÊĤ JAK P£- £- P 84 P 113 STAT complex 113 91 P 91 84 P 48inactive STAT Nuclear membrane ºËĤ P 113 P 91 84 P transcription 48 gene »ùÒò Interferons response element ¸ÉÈÅ Ó¦´ð Ôª¼þ ËØ
    72. 72. Interferon Dimerization of ReceptorAutophosphorylation of JAK Phosphorylation of STATNuclear translocation of STAT Interferon response element Expression of gene
    73. 73. 5. Nuclear factor-κB pathway
    74. 74. 6. TGF-βpathway
    75. 75. Intracellular receptor (DNA transcription regulated receptor)• Steroid H, VD3, Thyroxine• Cytosolic R: glycocorticosteroid H• Nuclear R: thyroxine, estrogen, androgen, progesterone
    76. 76. Serum binding proteinWith bound bormone

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