title: Rapid dephosphorylation of G protein-coupled receptors by protein phosphatase 1β is required for termination of β-arrestin-dependent signaling.
abstract: Termination of signaling of activated G protein-coupled receptors (GPCRs) is essential for maintenance of cellular homeostasis. It is well established that β-arrestin redistributes to phosphorylated GPCRs and thereby facilitates desensitization of classical G protein-dependent signaling. β-Arrestin in turn serves as a scaffold to initiate a second wave of signaling. Here, we report a molecular mechanism that regulates the termination of unconventional β-arrestin-dependent GPCR signaling. We identify protein phosphatase 1β (PP1β) as a phosphatase for the cluster of phosphorylated threonines ((353)TTETQRT(359)) within the sst(2A) somatostatin receptor carboxyl terminus that mediates β-arrestin binding using siRNA knock-down screening. We show that PP1β-mediated sst(2A) dephosphorylation is initiated directly after receptor activation at or near the plasma membrane. As a functional consequence of diminished PP1β activity, we find that somatostatin- and substance P-induced but not epidermal growth factor-induced ERK activation was aberrantly enhanced and prolonged. Thus, we demonstrate a novel mechanism for fine tuning unconventional β-arrestin-dependent GPCR signaling in that recruitment of PP1β to activated GPCRs facilitates GPCR dephosphorylation and, hence, leads to disruption of the β-arrestin-GPCR complex.
authors.affiliation: Institute of Pharmacology and Toxicology, University Hospital, Friedrich Schiller University, D-07747 Jena, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Pöll
authors.forename: Christian
authors.initials: C
authors.lastname: Doll
authors.forename: Stefan
authors.initials: S
authors.lastname: Schulz
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D055162:Biocatalysis / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008387:Marine Toxins; D008969:Molecular Sequence Data; D019319:Okadaic Acid / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D051381:Rats; D017481:Receptors, Somatostatin / Q000737:chemistry / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D008387:Marine Toxins; D010080:Oxazoles; D017481:Receptors, Somatostatin; D000071557:beta-Arrestins; C106140:somatostatin receptor sst2A; D019319:Okadaic Acid; D012694:Serine; C059041:calyculin A; D048049:Extracellular Signal-Regulated MAP Kinases; C517188:PPP1CB protein, human; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1