Beta-arrestin-recruited phosphodiesterase-4 desensitizes the AKAP79/PKA-mediated switching of beta2-adrenoceptor signalling to activation of ERK.
Using combined dominant-negative and siRNA (small interfering RNA)-mediated knockdown strategies, the functional importance of specific PDE4 (phosphodiesterase-4) isoforms in modifying signalling through the beta2-AR (beta2-adrenoceptor) has been uncovered. The PDE4D5 isoform preferentially interacts with the signalling scaffold protein beta-arrestin and is thereby recruited to the beta2-AR upon agonist challenge. Delivery of an active PDE to the site of cAMP synthesis at the plasma membrane specifically attenuates the activity of a pool of PKA (protein kinase A) that is tethered to the beta2-AR via AKAP79 (A-kinase anchoring protein 79). The specific functional role of this anchored PKA is to phosphorylate the beta2-AR and allow it to switch its coupling with G(i) and thereby activation of ERK (extracellular-signal-regulated kinase). Our studies uncover a novel facet of the regulation of beta2-AR signalling by showing that beta-arrestin-recruited PDE4 provides the means of desensitizing the agonist-dependent coupling of beta2-AR with G(i) and its consequential activation of ERK.
Houslay
M D
MD
Division of Biochemistry and Molecular Biology, IBLS, Wolfson Building, University of Glasgow, Glasgow G12 8QQ, Scotland, UK. M.Houslay@bio.gla.ac.uk
Baillie
G S
GS
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000071557:beta-Arrestins
D048868:Adaptor Proteins, Signal Transducing; D019390:Arrestins; D007527:Isoenzymes; D018343:Receptors, Adrenergic, beta-2; D000071557:beta-Arrestins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human