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A. Overview of G-Proteinsnavigator

  1. GTP binding proteins couple cell surface receptors to second signal mechanisms
  2. Receptors which interact with G-proteins are called G-protein coupled receptors (GPCR)
  3. Composed of three subunits
    1. alpha - binds GTP, loosely bound to beta-gamma; 16 distinct human alpha genes known
    2. beta - strongly bound to gamma; 6 human ß genes known
    3. Gamma - strongly bound to beta; 6 human gamma genes known
  4. Activity of Trimeric G Proteins
    1. Regulated by binding and hydrolysis of GTP
    2. GDP bound to alpha subnit is inactive and associates with beta-gamma dimer
    3. Ligand binding to GPCR leads to release fo GDP from alpha subunit (in trimer)
    4. GTP then binds to alpha subunit (associated with trimer)
    5. GTP binding to alpha leads to release of beta-gamma dimer
    6. This is the activation step: free beta-gamma dimer activates downstream receptors
  5. Signalling Through G Proteins
    1. Active portion of G-proteins consists of beta-gamma dimers (dissociated from alpha)
    2. Inhibition of GTP hydrolysis leads to blockade of beta-gamma dimer release
    3. Key differences in G protein complexes are due to alpha subtypes present
    4. Five distinct alpha subtypes are known
    5. Signalling through G-proteins may be positive or negative depending on the subtype
  6. G-alpha Subtypes
    1. G(s)alpha - increases cAMP synthesis
    2. G(i)alpha - inhibits cAMP synthesis, closes Ca2+ channels, opens K+ channels
    3. G(t)alpha - increases cGMP breakdown (photon effects in rod and cone cells)
    4. G(q)alpha - increases phosphoinositide synthesis, increases intracellular calcium
    5. G(13)alpha - stimulates Na+/H+ exchnage and cytoskeletal rearrangements

B. Diseases Due to G-Protein Alterationsnavigator

  1. Excessive Signalling (Defective Signal Termination)
    1. McCune-Albright Syndrome
    2. Pituitary and thyroid adenomas
    3. Adrenal and ovarian adenomas
    4. Cholera
  2. Defective Signalling (G-alpha Abnormalities)
    1. Pseudohypoparathyroidism
    2. Night Blindness
  3. Abnormal Signal Initiation (Inadequate or Excessive Signalling)
    1. Essential hypertension - mutations in G-ß3 protein
    2. Pseudohypoparathyroidism
    3. Testotoxicosis
    4. Pertussis

References navigator

  1. Farfel Z, Bourne HR, Iiri T. 1999. NEJM. 340(13):1012 abstract