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