Seven-Transmembrane Receptor Signaling
Heterotrimeric G-proteins & Second Messenger Pathways
7TM Receptor Interacting with Trimeric G-Protein
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 kinasesphosphorylate 7TMreceptors
• blocks further G proteinstimulation
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 GMPPhosphodiesterase
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