Carboxyl-Terminal Receptor Domains Control the Differential Dephosphorylation of Somatostatin Receptors by Protein Phosphatase 1 Isoforms

We have recently identified protein phosphatase 1β (PP1β) as G protein-coupled receptor (GPCR) phosphatase for the sst(2) somatostatin receptor using siRNA knockdown screening. By contrast, for the sst(5) somatostatin receptor we identified protein phosphatase 1γ (PP1γ) as GPCR phosphatase using the same approach. We have also shown that sst(2) and sst(5) receptors differ substantially in the temporal dynamics of their dephosphorylation and trafficking patterns. Whereas dephosphorylation and recycling of the sst(2) receptor requires extended time periods of ∼30 min, dephosphorylation and recycling of the sst(5) receptor is completed in less than 10 min. Here, we examined which receptor domains determine the selection of phosphatases for receptor dephosphorylation. We found that generation of tail-swap mutants between sst(2) and sst(5) was required and sufficient to reverse the patterns of dephosphorylation and trafficking of these two receptors. In fact, siRNA knockdown confirmed that the sst(5) receptor carrying the sst(2) tail is predominantly dephosphorylated by PP1β, whereas the sst(2) receptor carrying the sst(5) tail is predominantly dephosphorylated by PP1γ. Thus, the GPCR phosphatase responsible for dephosphorylation of individual somatostatin receptor subtypes is primarily determined by their different carboxyl-terminal receptor domains. This phosphatase specificity has in turn profound consequences for the dephosphorylation dynamics and trafficking patterns of GPCRs.