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Last lecture: reversible phosphorylation regulation of transcription This lecture:

Last lecture: reversible phosphorylation regulation of transcription This lecture: signal transduction. Fridays MC H313 Biological Sciences Seminar Series This Friday (19 th ): The smallest hormone: birth, life and many deaths of nitric oxide. Intracellular signal transduction:

imani-goodman
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Last lecture: reversible phosphorylation regulation of transcription This lecture:

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  1. Last lecture: reversible phosphorylation regulation of transcription This lecture: signal transduction

  2. Fridays MC H313 Biological Sciences Seminar Series This Friday (19th): The smallest hormone: birth, life and many deaths of nitric oxide

  3. Intracellular signal transduction: • receptors or sensors • second messengers • kinases, phosphatases, transcription factors • downstream targets (proteins)

  4. Intracellular Signal Transduction • Hormone receptors within the cell

  5. Intracellular receptors: • - cytosolic • - nuclear

  6. T4 T3

  7. Intracellular Signal Transduction • Hormone receptors within the cell • Hormone receptors on cell membrane (facing external environment)

  8. 2. Membrane receptors: - laterally mobile - interact with other membrane proteins - catalytic

  9. Intracellular Signal Transduction • Hormone receptors within the cell • Hormone receptors on cell membrane (facing external environment) • Signaling of entirely intracellular events

  10. 3. Detection & signaling of entirely intracellular events

  11. ATP ADP AMP ↑work →↑[AMP] AMP kinase ATP synthetic processes

  12. Intracellular Signal Transduction • Hormone receptors within the cell • Hormone receptors on cell membrane (facing external environment) • Signaling of entirely intracellular events

  13. Roles of signal transduction?

  14. Roles of signal transduction (1) Permit adaptation (2) Regulate response (3) Coordinate related events

  15. Features of signal transduction 1. Transduction 2. Amplification 3. Diversification 4. Transience

  16. Features of signal transduction 1. Transduction - conversion of one form to another 2. Amplification 3. Diversification 4. Transience

  17. Features of signal transduction 1. Transduction - conversion of one form to another 2. Amplification - one receptor/binding event can affect big changes 3. Diversification 4. Transience

  18. Features of signal transduction 1. Transduction - conversion of one form to another 2. Amplification - one receptor/binding event can affect big changes 3. Diversification - may affect related but different targets 4. Transience -

  19. Features of signal transduction 1. Transduction - conversion of one form to another 2. Amplification - one receptor/binding event can affect big changes 3. Diversification - may affect related but different targets 4. Transience - can be turned off

  20. An example of signal transduction: Receptors & G-proteins

  21. G-protein activated by binding GTP

  22. 1. Receptors that activate G-proteins • Largest family of receptors on cell surface (>1000 members) • Egs. epinephrine (adrenergic) receptor • Heterotrimers (one each of α, β, γ subunits) • Interact with a variety of effector molecules • Depend on lateral mobility of proteins in membrane

  23. Eg. G-protein acting via adenylyl cyclase (AC)

  24. In the cytosol:

  25. Mobilization of glucose subunits from glycogen: Hormone + receptor → G-protein → adenylyl cyclase → cAMP↑ → PKA → phosphoprotein kinase → glycogen phosphorylase

  26. G-proteins associated with phospholipase C and protein kinase C

  27. G-proteins can: Be stimulatory or inhibitory (eg. differential response to epinephrine) Have different actions; depends on: - particular combination of subunits (16 possible α isoforms; 5β; 11γ ) - presence of effectors nearby (egs. AC, phosphodiesterase, phospholipase) Affect changes in cAMP, Ca2+, diacylglycerol

  28. Receptors that are enzymes • Tyrosine kinases • Guanylyl cyclases • Catalyze cleavage (proteolysis) reactions (these may release an active transcription factor)

  29. Example 1: the insulin receptor Heterotetramer (2α and 2β subunits) β subunit is tyrosine kinase (autophosphorylates tyrosines on receptor, then on other proteins) Active IR stimulates PI 3-kinase activity GLUT4 protein recruited to membrane from intracellular vesicles

  30. Example 2: Nitric oxide receptor Has guanylyl cyclase activity: GTP → cGMP

  31. Protein regulation and signal transduction - summary and overview • Many strategies for altering specific and cellular activities • Fast vs slow responses • Specific activity vs amount of a protein • Protein kinases/phosphatases • Many transcription factors and HREs • Receptors: membrane, cytosol, nucleus • Receptor – effector mechanisms • Second messengers: signal amplification and/or diversification (egs. Ca++, cAMP, cGMP)

  32. Read chapter 3 for Thursday

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