Biochem Exam 2 (pt 4)

  1. Signal transduction across the membrane
    • Lipid membranes are efficient barriers that isolate cells from each other and the environment
    • Cells need to communicate and respond to challenges of their surrounding
    • Signals are recognized by cellular receptors (membrane bound or intracellular) and transduced into the cell
    • Transduced signals may be amplified to yield to required cellular response
  2. Steps of signal transduction (exception: steroid hormones)
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    • 1. External stimulus (signal molecules=first messengers)
    • 2. Reception of a first messenger and signal transduction to an effector enzyme=transfer of information across the membrane
    • 3. Transducer-relay signal to effector enzymes, which produce second messengers
    • 4. Activation of cytoplasmic and nuclear effectors that regulate protein activities
    • 5. Termination via inactivation of each step
  3. First messengers
    • Endocrine signals (hormones)
    • Autocrine and paracrine signals
    • Neurotransmitters
  4. Endocrine signals (hormones)
    Distant communication between organs and tissues in response to external or internal stimuli

    Long-living, distant action
  5. Insulin, glucagon
    Glucose metabolism, growth
  6. Steroid hormones
    Reproduction, stress, nutrient, water & mineral balance
  7. Growth hormones
    Proliferation, growth
  8. Autocrine and Paracrine signals
    • Secreted by common cells
    • Ex: growth factors; eicosanoids; gases- NO, CO, SH2

    Short living, local action
  9. Neurotransmitters
    • Communication between neuronal cells
    • Ex: serotonin, acetylcholine, glutamate, aspartate

    Short living, local action
  10. Receptors
    • Seven-transmembrane Helix receptors (7TM)
    • Dimerizing receptors
    • Receptor tyrosine kinases (RTK)
  11. Seven-transmembrane Helix receptors (7TM)
    • G-protein R-s
    • Activation: change conformation upon ligand binding 
    • ex: beta-andrenergic fight or flight response
  12. Dimerizing receptors
    • Extracellular domains of receptors bind the same molecule of hormone
    • Activation: dimerization
    • Ex: human growth hormone
  13. Receptor tyrosine kinases (RTK)
    • Receptor binding causes dimerization and cross-phosphorylation of the cytoplasmic domains
    • Activation: dimerization+self-phosphorylation 
    • Ex: growth factor receptors, insulin
  14. Second messengers
    • Cyclic adenosine monophosphate (cAMP)
    • Ca2+
    • Inositol-1,4,5-triphosphate (IP3)
    • Diacylglycerol (DAG)

    DAG and IP3 are produced upon hydrolysis of phosphorylated phosphatidylinositol
  15. Cyclic Adenosine Monophosphate (cAMP)
    • Binds and activates protein kinase A (PKA)
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    • Insitol 1,4,5-trisphosphate (IP3)
    • Has many targets
  17. Diacylglycerol (DAG)
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    • Activates protein kinase C and other targets
  18. G-protein receptors
    • Abundant (~800 human genes); targets for ~40% of medicinal drugs
    • Are protein complexes of a receptor (purpleO and the multi-subunit G-protein (a transducer): alpha (blue), beta (green) and gamma (yellow)
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  19. G-protein activity regulation
    • By binding of either GDP (inactive) or GTP (active) nucleotides to the alpha subunit
    • Ligand binding induces release of GDP from alpha subunit which binds GTP and dissociates from receptor and beta subunit in its active form!
  20. G protein cycle
    1) Ligand binding induces conformational changes in 7TMR and the release of GDP from alpha subunit. alpha binds GTP and dissociates from receptor and beta-gamma complex

    2) GTP-alpha subunit is active. It modulates activity of other proteins (i.e. adenylate cyclase-effector enzyme)

    3) Native GTPase activity of alpha slowly hydrolyzes GTP to GDP and alpha reassociates with the inhibitory beta-gamma complex
  21. Major target of activated G protein
    Adenylate cyclase
  22. What is cAMP inactivated by
    Phosphodiesterase
  23. Epinephrine/glucagon signaling
    "Fight or Flight" pathway via beta-adrenergic/glucagon receptor
  24. Caffeine
    Natural pesticide that protects plants or memory enhancer for pollinators but not efficient for spiders
  25. Dual role of caffeine
    • Blocks Adenosine receptors in the brain and on heart. This inhibits sedative effects of adenosine on the central neural system (CNS) and increases heart beat rate
    • Blocks phosphodiesterases so the signals from adrenaline (epinephrine) persist much longer (viagra works in a similar manner by inhibiting another phosphodiesterase)
  26. Phosphoinsitide signaling
    • Another GPCR pathway (via alpha-adreno receptors)
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  27. Two second messengers in phosphoinsitide signaling pathway
    • DAG and IP3
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  28. Role of Ca2+ in smooth muscle contraction
    • Calcium binding to EF hand motifs exposes hydrophobic methyl groups of methionine residues
    • These can now potentiate binding to amphiphilic helices on target proteins
    • Calmodulin's flexibility allows the molecule to "wrap around" its target
    • This allows tight binding to a wide range of different target proteins
    • Can bind and activate Myosin Light Chain Kinase (MLCK), which phosphorylates and activates myosin
    • Thus Ca2+ can  initiate smooth muscle contraction
  29. Receptor tyrosine kinases: Ras signaling
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  30. Lipid hormones bind to intracellular receptors
    • Activated steroid hormone receptors bind to transcription factors that directly regulate gene expression
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  31. Cholera Toxin (CT)
    • Modifies (ADP-ribosylates) the alpha-subunit of a G-protein.
    • This leads to permanent activation of adenylate cyclase and uncontrolled secretions of H2O, Na+, K+, Cl-, and HCO3- into the lumen of the small intestine

    As a result, untreated patients die from severe dehydration
  32. RAS small GTPase
    • Upon mutation, RAS is converted to constitutively active form- oncogen
    • Inhibits apoptosis, activates proliferation, migration and metastasis.

    All of these events support cancer
Author
Zaqxz
ID
349079
Card Set
Biochem Exam 2 (pt 4)
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