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.

阐明G蛋白偶联受体（GPCR）去磷酸化的分子机制仍然是一个重大挑战。尽管尚未鉴定出特定的GPCR磷酸酶（GRP），但现行模型建议受体必须首先内化到酸性内体中，才能在类似管家的过程中被去磷酸化。最近，磷酸位点特异性抗体与靶向特定磷酸酶转录物的siRNA结合，已经促进了将不同的蛋白质磷酸酶1（PP1）和PP2催化亚基鉴定为真正的GRP。与磷酸化相似，GPCR的去磷酸化在时间和空间上受到调节，从质膜上的受体激活后立即开始，并沿内吞途径继续。去磷酸化破坏受体-抑制蛋白复合物，从而终止依赖于抑制蛋白的信号传导。部分去磷酸化的GPCR可能会保持膜结合状态，从而重新激活激动剂，而其他的则会发生内吞作用。内化后，进一步的去磷酸化有助于过渡到回收途径，导致质膜重新聚集或溶酶体降解。这些发现揭示了受体去磷酸化的未知细胞部位和调节功能，并呼吁修订GPCR激活/失活周期模型。