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10-20-08_signalingGprotB0

10-20-08_signalingGprotB0 - The path(ways to enlightenment...

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The path(ways) to enlightenment: understanding intracellular signaling
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Announcements The quiz 3, question 2 grades have been corrected. A review session will be held in PHYS 223 from 5:30- 7:30 tomorrow (Tuesday).
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Nuthin’ but a G thang: G-protein coupled receptors 1000’s identified in all eukaryotes 7 transmembrane domain proteins with extracellular receptor coupled to trimeric (3 subunit) G-protein in the membrane Ligand binds within three extracellular loops Activation of G-protein eventually acts on effectors , which generate intracellular second messengers that potentially initiate multiple signaling pathways (signal cascades)
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Ligand binding to the GPCR shifts the receptor conformation Once the ligand is bound, the affinity for the G-protein increases At this point the G-protein has a bound GDP. The G-protein is bound to a trimeric complex consisting of alpha, beta, and gamma subunits Once bound to the receptor, GTP displaces GDP. A single activated receptor can activate many GDP-G-protein complexes, which can amplify a signal
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With GTP bound, the alpha subunit dissociates and moves in the membrane to an effector molecule The alpha and beta/gamma subunits break into 2 Subunits are held in membrane by covalent linkages to fatty acids Alpha subunit (Galpha) +GTP move to effector, which is adenylyl cylclase in this example Gbetagamma can also bind to a separate effector in some cases Adenylyl cyclase
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ATP alteration creates a second messenger Adenylyl cycles converts ATP to cyclic AMP (cAMP) cAMP is a common second messenger While the Galpha unit is bound to adenylyl cyclase, it will continue to form cAMP, which is another amplification step
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GTP eventually reverts back to GDP GTP hydrolysis usually occurs by a weak auto-catalysis This terminates formation of cAMP
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GDP+Galpha then dissociates from adenylyl cyclase and reforms with the Gbetagamma
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G-protein receptor kinases (GRK) are serine- threonine kinases that desensitize GPCRs GRKs use two ATP to phosphorylate the activated receptor. Desensitization is the cessation of the receptor response despite having bound ligand
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Arrestin binds to the two phosphates and prevents G-protein activation Arrestin prevents association of G-proteins with the activated receptor, so the G-protein can’t be activated by GTP.
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