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cellular signal transduction pathway

cellular signal transduction pathway

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cellular signal transduction pathway

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  2. cellular signal transduction pathway • G protein-mediated signal transduction • Tyrosine protein kinase-mediated signal transduction • Guanylate cyclase signal transduction pathway • Nuclear receptor-mediated signal transduction Www.ggene.Cn

  3. Effector  G  Signal G Protein Signal Cascade Www.ggene.Cn

  4. G-protein-coupled receptors Binding of ligands Extracellular -NH2 e3 e2 -S-S- e1 TM1 TM2 TM3 TM4 TM5 TM6 TM7 i2 i1 i3 Cytoplasmic Location of G Www.ggene.Cn COOH-

  5. 4 superfamilies  • binds GTP      G-protein subunits • Three subunits Www.ggene.Cn

  6. Diversity of G Protein-Coupled Receptor Signal Transduction Pathways Www.ggene.Cn

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  10. A G-protein that is part of a pathway that stimulates Adenylate Cyclase is called Gs & its a subunit Gsa.

  11. The sequence of events by which a hormone activates cAMP signaling: 1. Initially Gahas bound GDP, and αβ& γ subunitsare complexed together. Www.ggene.Cn

  12. 2.Hormone binding to a 7-helix receptor (GPCR) causes a conformational change in the receptor that is transmitted to the G protein. The nucleotide-binding site on Ga becomes more accessible to the cytosol, where [GTP] > [GDP]. Gareleases GDP & binds GTP (GDP-GTP exchange). Www.ggene.Cn

  13. 3.Substitution of GTP for GDP causes another conformational change in Ga. Ga-GTP dissociates from the inhibitory βγ complex & can now bind to and activate Adenylate Cyclase. Www.ggene.Cn

  14. 4. Adenylate Cyclase, activated byGa-GTP, catalyzes synthesis of cAMP. 5. Protein Kinase A (cAMP Dependent Protein Kinase) catalyzes phosphorylation of various cellular proteins, altering their activity. Www.ggene.Cn

  15. Protein Kinase A(cAMP-Dependent Protein Kinase) transfers Pi from ATP to OH of a Ser or Thr in a particular 5-amino acid sequence. Protein Kinase A in the resting stateis a complex of: • 2 catalytic subunits(C) • 2 regulatory subunits(R).R2C2 Www.ggene.Cn

  16. The domain of (R) binds to the active site of (C), blocking its activity. When each (R) binds 2 cAMP, a conformational change causes (R) to release (C). Each catalytic subunit can then catalyze phosphorylation of Ser or Thr on target proteins. R2C2 + 4 cAMP R2cAMP4 + 2 C

  17. Effects of PKA Ser/Thr残基磷酸化 (1)对代谢的调节作用 肾上腺素调节糖原分解 (2)对基因表达的调节作用 cAMP应答元件(CRE)基因调控区 cAMP应答元件结合蛋白(CREB)反式作用因子 PKA的催化亚基进入细胞后使CERB特定的Ser/Thr磷酸化,形成同源二聚体,结合DNA,激活转录 Www.ggene.Cn

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  19. Many enzymes are regulated by covalent attachment of phosphate, in ester linkage, to the side-chain hydroxyl group of a particular amino acid residue (serine, threonine, or tyrosine). Www.ggene.Cn

  20. A protein kinasetransfers the terminal phosphate of ATP to a hydroxyl group on a protein. • A protein phosphatase catalyzes removal of the Pi by hydrolysis. Www.ggene.Cn

  21. Protein kinases and phosphatases are themselves regulated by complex signal cascades. For example: • Some protein kinases are activated by Ca2+-calmodulin. • Protein Kinase A is activated by cyclic-AMP (cAMP). Www.ggene.Cn

  22. Turn off of the signal: 1. Ga hydrolyzes GTP to GDP + Pi. (GTPase). The presence of GDP on Ga causes it to rebind to the inhibitory βγ complex. Adenylate Cyclase is no longer activated. 2. Phosphodiesterasecatalyzes hydrolysis of cAMPAMP. Www.ggene.Cn

  23. Phosphodiesteraseenzymes catalyze: cAMP + H2OAMP The phosphodiesterase that cleaves cAMP is activated by phosphorylation catalyzed by Protein Kinase A. Thus cAMP stimulates its own degradation, leading to rapid turn off of a cAMP signal. Www.ggene.Cn

  24. Cyclic Nucleotide Metabolism - cAMP Www.ggene.Cn

  25. Turn off of the signal : 3. Hormone receptor desensitization occurs. This process varies with the hormone. • Some receptors are phosphorylated via G-protein-coupled receptor kinases. • The phosphorylated receptor may then bind to a protein arrestin that blocks receptor-G-protein activation & promotes removal of the receptor from the membrane by clathrin-mediated endocytosis. 4. Protein Phosphatase catalyzes removal by hydrolysis of phosphates that were attached to proteins via Protein Kinase A.

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  27. Phosphatidylinositol Signal Cascades phosphatidylinositol-4,5-bisphosphate (PIP2). PIP2 is cleaved by the enzyme Phospholipase C. Some hormones activate a signal cascade based on the membrane lipid phosphatidylinositol. Www.ggene.Cn

  28. Different isoforms of PLC have different regulatory domains, & thus respond to different signals. One form of Phospholipase C is activated by a G-protein, Gq. A GPCR (receptor) is activated. GTP exchanges for GDP. Gqa-GTP activates Phospholipase C. Www.ggene.Cn

  29. Cleavage of PIP2, catalyzed by Phospholipase C, yields two second messengers: inositol-1,4,5-trisphosphate (IP3) diacylglycerol (DG). Www.ggene.Cn

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  31. Diacylglycerol, with Ca++, activates Protein Kinase C, which catalyzes phosphorylation of several cellular proteins, altering their activity. Www.ggene.Cn

  32. Functions of PKC 1 对代谢的调节作用 Ser/Thr残基磷酸化 靶蛋白:质膜受体、膜蛋白和多种酶 2 对基因表达的调节作用 早期反应: expression of immediate-early gene 晚期反应 Www.ggene.Cn

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  34. IP3 activates Ca++-release channels in ER membranes. Ca++ stored in the ER is released to the cytosol, where it may bind calmodulin, or help activate Protein Kinase C. Signalturn-off includes removal of Ca++ from the cytosol via Ca++-ATPase pumps, & degradation of IP3. Www.ggene.Cn

  35. Ca2+-Calmodulin dependent protein kinases (CaM kinase) Extensive substrate for CaM kinase Phosphorylation of Ser/Thrresidues Activate AC, PDE, Nos, Ca2+-ATPase IP3 receptor PTP Www.ggene.Cn

  36. IP3 may instead be phosphorylated via specific kinases, to IP4, IP5 or IP6. Some of these have signal roles. E.g., the IP4 inositol-1,3,4,5-tetraphosphate in some cells activates plasma membrane Ca++ channels. Www.ggene.Cn

  37. Sequential dephosphorylation of IP3 by enzyme-catalyzed hydrolysis yields inositol, a substrate for synthesis of PI.. PI 3-Kinases instead catalyze phosphorylation of phosphatidylinositol at the 3 position of the inositol ring. PI-3-P, PI-3,4-P2, PI-3,4,5-P3, & PI-4,5-P2 have signaling roles.

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  39. Gq G12/13 Gi/o Gs         G-protein subtypes • inhibition of cAMP production • inhibition of Ca2+ channels • activation of GIRK K+ channels • mediates signalling between GPCRs and RhoA (GTPase) • function under investigation • increased synthesis of cAMP • activation of Ca2+ and K+ channels • activation of PLC leading to • activation of PKC (DAG) • intracellular Ca2+ release (IP3) Www.ggene.Cn

  40. GPCR signalling Www.ggene.Cn

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