Emerging Paradigms of G Protein-Coupled Receptor Dephosphorylation.

Elucidation of the molecular mechanisms underlying G protein-coupled receptor (GPCR) dephosphorylation remains a major challenge. While specific GPCR phosphatases (GRPs) have eluded identification, prevailing models propose that receptors must first internalize into acidic endosomes to become dephosphorylated in a housekeeping-like process. Recently, phosphosite-specific antibodies, combined with siRNAs targeting specific phosphatase transcripts, have facilitated the identification of distinct protein phosphatase 1 (PP1) and PP2 catalytic subunits as bona fide GRPs. Similar to phosphorylation, GPCR dephosphorylation is temporally and spatially regulated, starting immediately after receptor activation at the plasma membrane and continuing along the endocytic pathway. Dephosphorylation disrupts receptor-arrestin complexes, thus terminating arrestin-dependent signaling. Partially dephosphorylated GPCRs may remain membrane bound for renewed agonist activation while others undergo endocytosis. After internalization, further dephosphorylation facilitates the transition into the recycling pathway, leading to either plasma membrane repopulation or lysosomal degradation. These findings reveal unappreciated cellular sites and regulatory functions of receptor dephosphorylation and call for revised models of the GPCR activation/deactivation cycle.