Cell Signaling

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Cell Signaling
Lodish pgs. 534, 600, 618-619
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• A cell targeted by a particular chemical signal
  has a receptor protein that recognizes the signal
  molecule.

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• The response of a particular cell to a signal
  depends on the type of proteins it contains.

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Seven major classes of membrane receptors
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• Insulin is a key player in both carbohydrate and
  lipid metabolism, and has significant influences
  on protein and mineral metabolism.
• Defects in insulin signaling have widespread and
  devastating effects on many organs and tissues.
• The amino acid sequence is highly conserved
  among vertebrates, and many diabetic patients are
  treated with insulin extracted from pig pancreas.

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• Insulin regulates blood glucose levels by
  increasing import of glucose by fat and muscle
  cells.
• Glucose is liberated from dietary carbohydrate
  such as starch or sucrose by hydrolysis within
  the small intestine, and is then absorbed into
  the blood.

• When blood glucose rises above its normal level,
  pancreatic b-cells release insulin into the blood.

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• The insulin receptor is a dimeric tyrosine
  kinase embedded in the plasma membrane.
• Two alpha subunits-extracellular, have insulin
  binding domains.
• Two beta subunits linked by disulfide
  bonds-within and on cytosolic side of membrane.

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• Binding of insulin to the alpha subunits causes
  the beta subunits to phosphorylate themselves
  (autophosphorylation), thus activating the
  catalytic activity of the receptor.

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• Several intracellular proteins have been
  identified as phosphorylation substrates for the
  insulin receptor, the best-studied of which is
  insulin receptor substrate 1 or IRS-1.
• When IRS-1 is activated by phosphorylation, is
  serves as a type of docking center for
  recruitment and activation of other enzymes.

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• Activation of the insulin receptor will lead to
  the activation of the phosphatidylinositol-3
  kinase (PI-3K) pathway.
• This pathway will activate protein kinase B
  (PKB).
• PKB will inactivate glycogen synthetase 3 (GSK3)
  which normally inhibits glycogen synthase.
• When glycogen synthase is active, glucose
  monomers are synthesized into long chains of
  glycogen (liver and muscle).

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• Protein kinase B causes movement of the GLUT4
  glucose transporter from intracellular membranes
  to the cell surface.
• The influx of glucose will lower blood glucose
  levels.
• When blood glucose levels return to normal, the
  GLUT4 transporters will be taken back into the
  cell by endocytosis.

PKB
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• When glucose levels in the blood rise
• Your cells may be starved for energy.
• Over time, high blood glucose levels can hurt
  your eyes, kidneys, nerves, and/or heart.

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• Diabetes mellitus is a metabolic disease that is
  characterized by abnormally high levels of
  glucose in the blood.
• Type I or insulin-dependent diabetes is the
  result of a deficiency of insulin.
• It is due to destruction pancreatic b-cells,
  most likely the result of autoimmunity to one or
  more components of those cells.
• Usually begins in childhood.
• Many of the acute effects of this disease can be
  controlled by insulin replacement therapy.

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• Diabetes mellitus is a metabolic disease that is
  characterized by abnormally high levels of
  glucose in the blood.
• Type II or non-insulin-dependent diabetes begins
  as a syndrome of insulin resistance.
• Target tissues fail to respond appropriately to
  insulin.
• Typically, the onset of this disease is in
  adulthood.
• Despite monumental research efforts, the nature
  of the defect has been difficult to ascertain -
  in some patients, the insulin receptor is
  abnormal, in others, one or more aspects of
  insulin signaling is defective, and in others, no
  defect has been identified.
• The disease is controlled through dietary
  therapy and hypoglycemic agents.