Differential regulation of somatostatin receptor dephosphorylation by β-arrestin1 and β-arrestin2.

Signaling of G protein-coupled receptors (GPCRs) is tightly regulated by coordinated phosphorylation of intracellular serine and threonine residues. Although the mechanisms of agonist-induced phosphorylation have been deciphered for many GPCRs, the regulation of their dephosphorylation remains poorly understood. Using a combination of siRNA knockdown screening and phosphosite-specific antibodies, we have recently identified the catalytic subunit β of protein phosphatase 1 (PP1β) as major constituent of the GPCR phosphatase responsible for dephosphorylation of the sst2 somatostatin receptor. However, PP1-targeting subunits specifically required for GPCR dephosphorylation have not been identified so far. Here, we show that siRNA knockdown of β-arrestin1 strongly inhibits sst2 receptor dephosphorylation. Co-immunoprecipitation experiments demonstrate that β-arrestin1 and PP1β exist as constitutive complex that mediates rapid dephosphorylation of sst2 receptors at or near the plasma membrane. By contrast, β-arrestin2 is not essential for rapid sst2 receptor dephosphorylation. Together, these findings reveal a novel scaffolding function of β-arrestin1 that facilitates efficient targeting of PP1β to phosphorylated GPCRs.