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Seven-Transmembrane Receptor Signaling Heterotrimeric G-proteins & Second Messenger Pathways 7TM Receptor Interacting with Trimeric GProtein Canonical 7TM Signaling Pathway - I • Activated receptor • Binds heterotrimeric G-protein (G) – specific ones for specific receptors • Activated receptor is GEF – exchanges GDP for GTP on G – G dissociates from G • G activates/inhibits downstream transducers – adenylyl cyclases – phosphodiesterases – phospholipases • G activates/inhibits downstream transducers – inhibition of kinases that inactivate 7TM receptors Canonical 7TM Signaling Pathway – II • Adenylyl cyclase – synthesis if cAMP ([cAMP] increase 100X) – cAMP activates protein kinase A (PKA) • PKA (S/T kinase) – regulated by RII (regulatory II) subunit • RII subunit is binds cAMP or PKA catalytic subunit – deregulation by cAMP allows PKA to phosphorylate numerous substrates – PKA can enter nucleus and phosphorylate many transcriptions factors • activates and inhibits Canonical 7TM Signaling Pathway – III • Turning off the signals – RGS – regulators of G-protein signaling) • GAPs for G subunits that stimulate GTP hydrolysis • hydrolysis allows G reassociation – downstream kinases phosphorylate 7TM receptors • blocks further G protein stimulation Cyclic Nucleotides Adenylyl Cyclase • Converts ATP to cAMP • Stimulated by Gs • Inhibited by Gi Removal of Cyclic Nucleotides • Phosphodiesterases cut 3'-O-P bond to generate 5' nucleoside monophosphates • cAMP AMP • cGMP Phosphodiesterase GMP Cyclic Nucleotide Activated Kinases • Protein kinases – PKA • cAMP • cAMP binds to RII subunit • releases PKA from autoinhibition – PKG • cGMP -Andrenergic Receptors Formation of Lipid 2nd Messengers Lipid Second Messengers & Targets Lipid 2nd Messenger Activated Protein Kinases • Protein Kinase C Family Phosphoinositol Second Messenger Signaling Ca2+ Second Messenger Signaling Odorant Receptors Photoreceptors Eicosanoids