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.