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  1. GPCR superfamily is considered...
    • the largest known receptor family
    • constitutes more than 1% of the human genome 
  2. what does GPCR comprises receptors of?
    • a diverse array of molecules: 
    • nt, odorants, lipids, neuropeptides, large glycoprotein hormones
    • odorant receptor family alone contains 100s of genes 
  3. what are the mammalian GPCR? any subfamilies? 
    • nearly 300 diff. kinds
    • 3 main subfamilies: 
    • 1. Rhodopsin-like group (most of GPCRs)
    • 2. Glucagon-like pump
    • Metabotropic glutamate (mGli) and GABAB receptor family 
  4. how are the 3 subfamilies grouped? 
    according to >20% of sequence homology 
  5. what are orphan receptors? 
    • each GPCR family contains this
    • ID as membrans of GPCR superfamily by homology cloning but activating ligand is unknown
  6. what does α contains?
    contains GTP/GDP binding site which is responsible for identity
  7. β and γ subunits are...
    identical in vitro; most are ubiquitously expressed; anchor thru prenylation of Gβ
  8. Golf are exprssed in...
    olfactory bulb, coupled to PLCβ
  9. GT are...
    • coupled to cGMP phosphodiesterase and expressed in rod cells of retina 
    • cells inactivate by light
  10. Where are the N terminal and the C terminal located? 
    N terminal located on extracellular and C terminal on the intracellular
  11. Glucagon-like family.  describe them 
    • structurally similar to family 1, except larger N terminal domain (contains multiple potential S-S bridges) 
    • most ligands binding to receptors are peptides or glycprotein hormones
    • 30-40 residues
    • interaction with receptor over large surface area 
  12. family 3: mGluR/GABAB family. describe
    • extremely large extraceullar N terminal ligand binding domain 
    • highly ocnserved 3rd short intracellular loop
    • shares ~12% sequence homology with that of family 1, but overall transmembrane topology is similar
    • forms dimers 
  13. GABAB receptor forms ...
    • deterodimers between GABAB R1 and GABABR2 thru coiled regions in C-terminal tails 
    • required for effiicient cell surface expression and signalling 
  14. How is metabotropic glutamate receptors dimerization stabilized? 
    by disulfide bonds in N terminal extracellular domain 
  15. What is GPCR? 
    • larger family of receptorswith prbable common evolutionary precursor.  transmembrane protein that is serpentine in shape, crossing lipid bilayer 7x
    • 7 transmembrane domain
  16. G proteins are...
    • Guanine nucleotide binding proteins; 
    • in GTP mediated interactions 
  17. common feature of G protein 
    • bind GDP and GTP with high affinity, but 
    • GTP bound complex - high affinity for other proteins, affect enzymatic activity
    • possess intrinsic GTPase activity thats activated by interaction with regulatory proteins (GAPs) 
  18. GAPs
    GTPae activating proteins, that function on small GTP binding proteins 
  19. GEFs
    Guanine-nucleotide Exchange Factors that promote GDP release 
  20. RGSs
    regulations of G-protein signaling, similar to GAPs but act on heterotrimeric G proteins 
  21. G protein, common way to bind to GTP
    myristoylation, palmitoylation; linked to phospholipid tails (or lipid rafts) 
  22. what are the major groups of G proteins? 
    • small GTP binding proteins 
    • heterotrimeric G-proteins
  23. small GTP binding proteins 
    • act downstream of receptor: ras, rac, etc
    • growth ffactor receptor signaling? 
  24. heterotrimeric G-proteins 
    • directly coupled to receptor and enzyme 
    • coupled to 7 transmembrane spanning receptors
    • all are heterotrimeric, consist of α, β, and γ subunits 
  25. How does using toxins (or getting rid of it) helps? 
    helps understand
  26. cholera-toxin: 
    causes ADP-ribosylation of Gα, then release of GTP inhibited, then Gα trapped in active form.  cAMP regulates secretion of fluid to intestinum, enormous loss of liquid and electrolytes = death 
  27. Pertussis toxin 
    cuases ADP ribosylation of Gα release of GDP inhibit, the Gα locked in inactive form, then cant inhibit AC 
  28. drug-receptor interaction is?
    agonists vary in binding affinity for GPCR
  29. efficacy is?
    how well drug causes conformational change in receptor to activate G proteins 
  30. what type of agonists are there? 
    • partial or full with different binding affinities 
    • **agonist causes inactivation 
  31. mechanism of conformation change? 
    • is highly conserved
    • contraining intermolecular interactions that keep receptors preferentially silent in absence of agonist, between TM5&6, and between TM3&7
    • eg. DRY motif in TM3 
  32. what happens upon receptor activation? 
    • arg is proteinated
    • adjacent resides move 
    • tiliting the TM helix
    • increase exposes previously hidden sequences, which interact with G protein

    ***exact aa sequence responsible - difficult to pinpoint 
  33. mutations ...
    REFER back to slides? 
Card Set:
2012-11-01 00:09:55

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