Your SlideShare is downloading. ×
Third messanger
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×

Introducing the official SlideShare app

Stunning, full-screen experience for iPhone and Android

Text the download link to your phone

Standard text messaging rates apply

Third messanger

2,082
views

Published on

Published in: Technology

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
2,082
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
77
Comments
0
Likes
0
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide
  • 图 16-3 含 TPK 结 构 域 的 受 体
  • Transcript

    • 1. Chapter 15Cellular Signal Transduction The biochemistry and molecular biology department of CMU
    • 2. When environment changes: Monad——responds directly. Multicellular organisms——signalthrough elaborate system ofintercellular or intracellularcommunication , and consequentlyregulate functions of organisms.
    • 3. Signaling moleculeReceptor of target cell Signal transductionIntracellular molecule biological effect
    • 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 moleculesprotein & peptides: Hormone, cytokineAA & its derivatives: Gly, Glu, adrenaline, thyroxineSteroid: Sex Hormone, glucocorticosteroidFatty 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• Ca2+ ions• DG, ceramide lipid derivatives• IP3 carbohydrate derivatives• cAMP cGMP nucleotides• Ras, JAK, Raf proteins
    • 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. 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. 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. §2 Receptor
    • 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. 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. membrane receptors(1) Ligand-gate ion channels type (cyclic receptor) ligand→receptor→ion channel open orclose
    • 23. (2) G Protein-Coupled Receptors (serpentine R)1) 7-helices transmembranereceptor
    • 24. Oligosaccharide unitCytosolic side
    • 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. 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. Glucagonβ-adrenaline →α s →AC↑ACTHα-adrenalineangiotensin Ⅱ →α i→AC↓acetylcholine(M2 M4)GF release inhibitory factor
    • 28.  
    • 29. Cholera toxinRibosylation of Arg of Gα ATPaseG α s -ATP Gα s -ADP ACcAMP Cl- + H2O Cavity of intestine HCO3- diarrhea
    • 30. Pertussis toxinα i -ADP-ribosylation Gi AC↑ cAMP ↑allergy of histamine
    • 31. 4) Effect proteins of G protein AC cGMP PDE (phosphodiesterase ) PLC PLA2 Channel protein
    • 32. cAMPATP
    • 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. (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. Tyrosine protein kinase Receptor or receptor tyrosine kinase (RTK) Cys-rich domain Immunoglobulin -like domainEGFR IGF-1R PDGFR FGFR
    • 36. Insulin IntracellularCytosol insulin effects
    • 37. Non-receptor tyrosine kinase (NRTK)
    • 38. Domain of Downstream molecules of TPKRSH2 domain (Scr homology 2 domain)SH3 domainPH domain (pleckstrin homology domain)
    • 39. (4) Guanylate cyclase (GC) receptorMembrane receptor –ANPSoluble receptor – NO, CO
    • 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. 3. Properties of binding of H and R• highly specificity• highly affinity• saturation• reversible binding• special function model
    • 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. §3 Pathway of Signal Transduction
    • 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. 1. cAMP dependent-protein kinase A pathway H R G protein AC cAMP PKAPhosphorylation of Es or functional proteins Biological effects
    • 47. (1) cAMP metabolism AC PDEATP 2+ cAMP 2+ 5-AMP Mg Mg PPi H2OPDE : PhosphodiesteraseAC : Adenylate cyclase
    • 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. (2) Mechanism of cAMP effect Activate cAMP-dependentprotein kinase (PKA).
    • 50. (3) PKA effect
    • 51. Phosphorylate specifically Ser/Thr residues in severalproteins ( 1 ) Regulation ofmetabolism ( 2 ) Regulation of geneexpression
    • 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. CRE : cAMP response element (TGACGTCA)CREB: CRE binding protein
    • 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. 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. [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. 1 ) Function of DG and IP3 IP3 + R→open of Ca2 +channel →[Ca2 + ]↑ DG PKC ↑ PS, Ca2 +
    • 58. 2 ) Function of PKC• regulation of metabolism PKC →Ser/Thr-P of R, enzyme, Protein of Mb.• Gene expression  
    • 59. Early response: PKC Trans-acting factor-PImmediate early genes Third messenger Late response: PKC Third messenger-P Activate genes Cell proliferation
    • 60. (2) Ca2 + -CaM dependent proteinkinase pathwayH R G protein PLC IP3 Ca2+ CaM CaMK Phosphorylation of Es or functional proteins Biological effects
    • 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. 3. cGMP-dependent PKG pathway ANP NO, CO Receptor- linked GC cGMP Soluble GC PKGPhosphorylation of Es or functional proteins Biological effects
    • 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. ANP ( atrial natriureticpeptides ) ↓ GC NO ↓ cGMP ↓ PKG ↓Vascular dilatation
    • 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. 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. (1) Receptor TPK - Ras - MAPK pathway• GRB2, SOS, Ras, Raf• Small G protein: Ras• MAPK (mitogen-activated protein kinase) : MAPK 、 MAPKK 、 MAPKKK
    • 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. (2) JAKs - STAT pathway ligand non TPK receptor JAKs STAT gene expression
    • 70. • JAKs• STAT: Signal transductors and activator of transcription
    • 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. Interferon Dimerization of ReceptorAutophosphorylation of JAK Phosphorylation of STATNuclear translocation of STAT Interferon response element Expression of gene
    • 73. 5. Nuclear factor-κB pathway
    • 74. 6. TGF-βpathway
    • 75. Intracellular receptor (DNA transcription regulated receptor)• Steroid H, VD3, Thyroxine• Cytosolic R: glycocorticosteroid H• Nuclear R: thyroxine, estrogen, androgen, progesterone
    • 76. Serum binding proteinWith bound bormone