Updated: 4/9/2020

Signal Transduction

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Tyrosine kinase signalling
  • Tyrosine kinase structure
    • dimeric transmembrane protein
    • intrinsic kinase activity
    • phosphorylated receptor can bind protein called insulin receptor substrate (IRS)
      • is a scaffold protein
  • Pathway
    • hormone binds to receptor
    • receptor is dimerized
    • auto cross-phosphorylation of intracellular domain of the dimerized receptor
    • IRS binds phosphorylated domian
    • IRS is phosphorylated on SH2-domains
    • several enzymes bind phosphorylated SH2-domians
      • phosphatases
        • pathway signaled for by insulin
      • kinases
        • phosphoinositol-3 (PI-3) kinase
      • G proteins
        • ras
          • oncogene present in many cancer
          • constitutive activation leads to constant growth signal
  • Examples
    • insulin, PDGF, EGF receptors
    • sensitization via PPAR-gamma 
G protein signalling
  • G-protein structure
    • trimeric enzyme
      • α, β, γ
        • α-subunit has intrinsic GTPase activity
          • acts as timer for shutting off the active form
  • Pathway
    • hormone binds to receptor:G-protein complex on cell membrane
    • GDP bound to inactive α-subunit is exchanged for GTP
    • α-subunit now active
      • can be inhibitory (Gi) or stimulatory (Gs, Gq)
    • is released from β, γ subunits
    • can act as 2 different effector mechanisms
      • cAMP pathway
        • Gs activates adenyl cyclase
          • normally, ATP → cAMP to increase [cAMP]
          • cAMP can activate protein kinase A
          • Cholera and E. coli toxins
            • ADP-ribosylates subunit of Gs, which activates G
            • ↑↑↑ [cAMP]
        • Gi inhibits adenyl cyclase
          • normally, stops ATP → cAMP to decreases [cAMP]
          • Pertussis toxin
            • ADP-ribosylates subunit of Gi, which inhibits Gi
            • ↑↑↑ [cAMP]
      • PIP2 pathway
        • Gq activates phospholipase C
          • PIP2 → IP3 + DAG
            • DAG can activate protein kinase C
            • IP3 can release Ca2+ from the ER
              • Ca2+ then activates a number of enzymes including protein kinase C
    • GTP eventually hydrolyzed to GDP and α-subunit becomes inactive
  • Examples
    • cAMP = glucagon, epinephrine (β, α2)
    • PIP2 = vasopressin, epinephrine (α1)
    • full list given in G-protein-linked 2nd messengers topic
 
cGMP signalling
  • Pathway
    • hormone binds to receptor on cell membrane
      • there is also a soluble receptor in the cytoplasm
    • receptor has intrinsic guanylate cyclase activity
      • GTP → cGMP
        • cGMP activate protein kinase G
          • protein kinase G mediates smooth muscle relaxation/vasodilation
      • no G protein required
  • Examples
    • ANF → cell membrane receptor
    • NO → diffuses across cell membrane and binds soluble receptor
      • mechanism for pharmacologic nitrates (nitroprusside, nitroglycerine)

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