Transcript Seven-Transmembrane Receptor Signaling

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