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 β2-AR (β2-adrenoceptor) has been uncovered. The PDE4D5 isoform preferentially interacts with the signalling scaffold protein β-arrestin and is thereby recruited to the β2-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 β2-AR via AKAP79 (A-kinase anchoring protein 79). The specific functional role of this anchored PKA is to phosphorylate the β2-AR and allow it to switch its coupling with Gi and thereby activation of ERK (extracellular-signal-regulated kinase). Our studies uncover a novel facet of the regulation of β2-AR signalling by showing that β-arrestin-recruited PDE4 provides the means of desensitizing the agonist-dependent coupling of β2-AR with Gi and its consequential activation of ERK.
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October 2005
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Conference Article|
October 26 2005
β-Arrestin-recruited phosphodiesterase-4 desensitizes the AKAP79/PKA-mediated switching of β2-adrenoceptor signalling to activation of ERK
M.D. Houslay;
M.D. Houslay
1
1Division of Biochemistry and Molecular Biology, IBLS, Wolfson Building, University of Glasgow, Glasgow G12 8QQ, Scotland, U.K.
1To whom correspondence should be addressed (email M.Houslay@bio.gla.ac.uk).
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G.S. Baillie
G.S. Baillie
1Division of Biochemistry and Molecular Biology, IBLS, Wolfson Building, University of Glasgow, Glasgow G12 8QQ, Scotland, U.K.
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Biochem Soc Trans (2005) 33 (6): 1333–1336.
Article history
Received:
June 14 2005
Citation
M.D. Houslay, G.S. Baillie; β-Arrestin-recruited phosphodiesterase-4 desensitizes the AKAP79/PKA-mediated switching of β2-adrenoceptor signalling to activation of ERK. Biochem Soc Trans 26 October 2005; 33 (6): 1333–1336. doi: https://doi.org/10.1042/BST0331333
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