Emerging Paradigms of G Protein-Coupled Receptor Dephosphorylation. (July 2017)

• Record Type: Journal Article
• Authors: Kliewer, Andrea; Reinscheid, Rainer K.; Schulz, Stefan
• Is Part Of: Trends in pharmacological sciences. Volume 38:Number 7(2017)
• Page Start: 621
• Page End: 636
• Publication Date: 2017-07
• Subjects: G protein-coupled receptor -- β2-adrenoceptor -- somatostatin receptor -- desensitization -- resensitization -- phosphorylation -- dephosphorylation -- internalization; Pharmacology -- Periodicals; Pharmacology -- trends -- Periodicals; Pharmacologie -- Périodiques; Pharmacology; Electronic journals; Periodicals; 615.1
• DOI: 10.1016/j.tips.2017.04.002
• Languages: English
• ISSNs: 0165-6147

Abstract

Abstract : 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. Trends: Dephosphorylation is an integral part of the G protein-coupled receptor (GPCR) activation/deactivation cycle and essential for receptor resensitization. However, comparably little is known about the specific protein phosphatases (PPs), kinetic and structural parameters, subcellular localization, and functional contributions of accessory proteins involved in GPCR dephosphorylation. Recent advances using phosphosite-specific antibodies combined with systematic siRNA knockdown have matched specific phosphatase catalytic subunits from the PP1 and PP2 families with several GPCRs. The GPCR–arrestin complex recruits a specific phosphatase immediately after agonist activation and dephosphorylation continues along the endocytic pathway. GPCR dephosphorylation is also necessary for termination of arrestin-dependent signaling. Early in vivo studies have linked GPCR dephosphorylation with physiological functions such as analgesic tolerance (opioid receptors), thyroid function (thyrotropin-releasing hormone receptor), and diminished drug responsiveness of endocrine tumors (somatostatin receptors).