Targeting of cyclic AMP degradation to beta 2-adrenergic receptors by beta-arrestins.
Catecholamines signal through the beta2-adrenergic receptor by promoting production of the second messenger adenosine 3',5'-monophosphate (cAMP). The magnitude of this signal is restricted by desensitization of the receptors through their binding to beta-arrestins and by cAMP degradation by phosphodiesterase (PDE) enzymes. We show that beta-arrestins coordinate both processes by recruiting PDEs to activated beta2-adrenergic receptors in the plasma membrane of mammalian cells. In doing so, the beta-arrestins limit activation of membrane-associated cAMP-activated protein kinase by simultaneously slowing the rate of cAMP production through receptor desensitization and increasing the rate of its degradation at the membrane.
Perry
Stephen J
SJ
Howard Hughes Medical Institute, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Baillie
George S
GS
Kohout
Trudy A
TA
McPhee
Ian
I
Magiera
Maria M
MM
Ang
Kok Long
KL
Miller
William E
WE
McLean
Alison J
AJ
Conti
Marco
M
Houslay
Miles D
MD
Lefkowitz
Robert J
RJ
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D009154:Mutation; D011233:Precipitin Tests; D051381:Rats; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection; D000071557:beta-Arrestins
D000318:Adrenergic beta-Agonists; D019390:Arrestins; D007527:Isoenzymes; D018343:Receptors, Adrenergic, beta-2; D011993:Recombinant Fusion Proteins; D000071557:beta-Arrestins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D007545:Isoproterenol