Signal Transduction

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Signal Transduction
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I. G Protein-Coupled Receptors(GPCRs)

• gt 1000 different mammalian GPCR genes
• 60 of drugs target GPCRs
• Membrane spanning domains consist of 7 helices
• Bind
• hormones (e.g, epinephrine)
• odorant molecules
• eicosanoids
• First to be characterized rhodopsin

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II. Heterotrimeric G Proteins

• Bind GTP and GDP hydrolyze GTP to GDP Pi
• Consist of ?, ?, and ? subunits
• G? contains NT binding site in cleft
• G? and G? dissociate only under denaturing
  conditions (G??)
• Inactive state G? binds GDP (G??GDP-G??)
• Binding of GPCR to ligand causes exchange of GDP
  for GTP in G protein G??GTP dissociates from G??
• Activated G proteins are short-lived because G?
  also has GTPase activity (see cholera and
  pertussin toxins)
• Typical mammalian cell contains many different
  combinations of subunits
• Major target adenylate cyclase
• Some G proteins stimulate AC (Gs?)
• Some inhibit AC (GI?)

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III. Adenylate CyclaseProduction of a SECOND
MESSENGER

• ATP ? cAMP PPi

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Drugs/toxins increase cAMP

• Caffeine, theophylline, theobromine are agonists
  for adenosine receptors

Cholera toxin binds to a membrane ganglioside,
allowing entry of toxic peptide fragment into
target cell. Arg in Gs? is ADP-ribosylated (from
NAD), activating adenylate cyclase.
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IV. Receptor Tyr Kinases (RTKs)

• Insulin, growth factors act through RTKs
• Usually single transmembrane region
• Exist as monomers until ligand binds, then
  proteins dimerize (except insulin)
• Autophosphorylation of cytosolic Tyr-containing
  domains
• These poly-phosphorylated kinases then
  phosphorylate other proteins
• (There are many protein phosphatases that reverse
  the cascades described)

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(And some protein growth factors)
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V. The Phosphoinositide Pathway
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PI pathway, continued

• IP3 diffuses through cytosol to ER, where it
  binds to a receptor, which is also an ion channel
• Ca2, stored in the ER, is released, eliciting
  wide-ranging cellular and extracellular responses
  (muscle contraction, glucose mobilization)
• DAG activates PKC, a cytosolic kinase
• When activated, PKC associates with membrane
• Many isoforms of PKC exist

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Phorbol esters bind in a groove near the DAG
binding site.