Arrestin Scaffolds NHERF1 to the P2Y12 Receptor to Regulate Receptor Internalization

Nisar, Shaista P.; Cunningham, Margaret; Saxena, Kunal; Pope, Robert J P; Kelly, Eamonn; Mundell, Stuart J

doi:10.1074/jbc.m112.347104

Cited by 32 publications

(79 citation statements)

References 39 publications

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“…NHERF1 overexpression also rescues the endocytosis of an internalization-defective platelet-activating factor receptor and antagonizes platelet-activating factor receptor-mediated inositol phosphate formation . Agonist activation of the purinergic P2Y 12 receptor results in the b-arrestin-dependent recruitment of NHERF1 to the receptor and promotes the formation of a P2Y 12 receptor/ NHERF1 complex that does not require PDZ-binding motif interactions (Nisar et al, 2012). NHERF1 also regulated frizzled family receptor activity (Wheeler et al, 2011).…”

Section: Membrane-associated Guanylate Kinase With Inverted Orientatimentioning

confidence: 99%

PDZ Protein Regulation of G Protein–Coupled Receptor Trafficking and Signaling Pathways

Dunn

Ferguson

2015

Mol Pharmacol

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G protein-coupled receptors (GPCRs) contribute to the regulation of every aspect of human physiology and are therapeutic targets for the treatment of numerous diseases. As a consequence, understanding the myriad of mechanisms controlling GPCR signaling and trafficking is essential for the development of new pharmacological strategies for the treatment of human pathologies. Of the many GPCR-interacting proteins, postsynaptic density protein of 95 kilodaltons, disc large, zona occludens-1 (PDZ) domain-containing proteins appear most abundant and have similarly been implicated in disease mechanisms. PDZ proteins play an important role in regulating receptor and channel protein localization within synapses and tight junctions and function to scaffold intracellular signaling protein complexes. In the current study, we review the known functional interactions between PDZ domain-containing proteins and GPCRs and provide insight into the potential mechanisms of action. These PDZ domain-containing proteins include the membraneassociated guanylate-like kinases [postsynaptic density protein of 95 kilodaltons; synapse-associated protein of 97 kilodaltons; postsynaptic density protein of 93 kilodaltons; synapse-associated protein of 102 kilodaltons; discs, large homolog 5; caspase activation and recruitment domain and membrane-associated guanylate-like kinase domain-containing protein 3; membrane protein, palmitoylated 3; calcium/calmodulin-dependent serine protein kinase; membrane-associated guanylate kinase protein (MAGI)-1, MAGI-2, and MAGI-3], Na 1 /H 1 exchanger regulatory factor proteins (NHERFs) (NHERF1, NHERF2, PDZ domaincontaining kidney protein 1, and PDZ domain-containing kidney protein 2), Golgi-associated PDZ proteins (Ga-binding protein interacting protein, C-terminus and CFTR-associated ligand), PDZ domain-containing guanine nucleotide exchange factors (GEFs) 1 and 2, regulator of G protein signaling (RGS)-homology-RhoGEFs (PDZ domain-containing RhoGEF and leukemia-associated RhoGEF), RGS3 and RGS12, spinophilin and neurabin-1, SRC homology 3 domain and multiple ankyrin repeat domain (Shank) proteins (Shank1, Shank2, and Shank3), partitioning defective proteins 3 and 6, multiple PDZ protein 1, Tamalin, neuronal nitric oxide synthase, syntrophins, protein interacting with protein kinase C a 1, syntenin-1, and sorting nexin 27.

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Section: Membrane-associated Guanylate Kinase With Inverted Orientatimentioning

confidence: 99%

PDZ Protein Regulation of G Protein–Coupled Receptor Trafficking and Signaling Pathways

Dunn

Ferguson

2015

Mol Pharmacol

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“…A critical role for PDZ-type ligands in receptor traffic has been identified for many GPCRs (6,[8][9][10]. For example, studies with the β 2 AR demonstrate that removal of the PDZ ligand of this receptor results in impaired recycling and enhanced lysosomal degradation (9).We have recently demonstrated the role of the PDZ ligand in P2Y 12 function (11,12). Importantly, we identified a novel naturally occurring heterozygous missense mutation in the cDNA of P2Y 12 isolated from a patient suffering a mild bleeding disorder (11,13,14).…”

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confidence: 98%

“…While some GPCRs, such as the protease-activated receptor (PAR) family, become degraded upon internalization (1), most are efficiently recycled back to the plasma membrane. Studies from our laboratory investigating purinergic GPCR function in human platelets have demonstrated efficient internalization, desensitization and rapid resensitization of P2Y 12 in response to ADP (2)(3)(4). Exposure of platelets to ADP results in simultaneous activation of P2Y 1 and P2Y 12 receptors, which couple to G q and G i , respectively, and act synergistically to mediate platelet activation and aggregation (5).…”

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confidence: 99%

“…Studies from our laboratory investigating purinergic GPCR function in human platelets have demonstrated efficient internalization, desensitization and rapid resensitization of P2Y 12 in response to ADP (2)(3)(4). Exposure of platelets to ADP results in simultaneous activation of P2Y 1 and P2Y 12 receptors, which couple to G q and G i , respectively, and act synergistically to mediate platelet activation and aggregation (5). The regulation of P2Y 12 is G protein-coupled receptor kinase (GRK) dependent with subsequent recruitment to clathrin-coated pits (CCPs) in an arrestin-dependent manner (3,6).…”

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confidence: 99%

“…Exposure of platelets to ADP results in simultaneous activation of P2Y 1 and P2Y 12 receptors, which couple to G q and G i , respectively, and act synergistically to mediate platelet activation and aggregation (5). The regulation of P2Y 12 is G protein-coupled receptor kinase (GRK) dependent with subsequent recruitment to clathrin-coated pits (CCPs) in an arrestin-dependent manner (3,6). Following internalization and receptor dephosphorylation, P2Y 12 receptors are recycled back to the plasma membrane (2).…”

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Differential Endosomal Sorting of a Novel P2Y₁₂ Purinoreceptor Mutant

Cunningham

Nisar

Cooke

et al. 2013

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P2Y 12 receptor internalization and recycling play an essential role in ADP-induced platelet activation. Recently, we identified a patient with a mild bleeding disorder carrying a heterozygous mutation of P2Y 12 (P341A) whose P2Y 12 receptor recycling was significantly compromised. Using human cell line models, we identified key proteins regulating wild-type (WT) P2Y 12 recycling and investigated P2Y 12 -P341A receptor traffic. Treatment with ADP resulted in delayed Rab5-dependent internalization of P341A when compared with WT P2Y 12 . While WT P2Y 12 rapidly recycled back to the membrane via Rab4 and Rab11 recycling pathways, limited P341A recycling was observed, which relied upon Rab11 activity. Although minimal receptor degradation was evident, P341A was localized in Rab7-positive endosomes with considerable agonist-dependent accumulation in the trans-Golgi network (TGN). Rab7 activity is known to facilitate recruitment of retromer complex proteins to endosomes to transport cargo to the TGN. Here, we identified that P341A colocalized with Vps26; depletion of which blocked limited recycling and promoted receptor degradation. This study has identified key points of divergence in the endocytic traffic of P341A versus WT-P2Y 12 . Given that these pathways are retained in human platelets, this research helps define the molecular mechanisms regulating P2Y 12 receptor traffic and explain the compromised receptor function in the platelets of the P2Y 12 -P341A-expressing patient. The trafficking of G protein-coupled receptors (GPCRs) involves a series of highly coordinated events. While some GPCRs, such as the protease-activated receptor (PAR) family, become degraded upon internalization (1), most are efficiently recycled back to the plasma membrane. Studies from our laboratory investigating purinergic GPCR function in human platelets have demonstrated efficient internalization, desensitization and rapid resensitization of P2Y 12 in response to ADP (2-4). Exposure of platelets to ADP results in simultaneous activation of P2Y 1 and P2Y 12 receptors, which couple to G q and G i , respectively, and act synergistically to mediate platelet activation and aggregation (5). The regulation of P2Y 12 is G protein-coupled receptor kinase (GRK) dependent with subsequent recruitment to clathrin-coated pits (CCPs) in an arrestin-dependent manner (3,6). Following internalization and receptor dephosphorylation, P2Y 12 receptors are recycled back to the plasma membrane (2). Efficient recycling of both P2Y 1 and P2Y 12 receptors is required for the maintenance of receptor responsiveness to ADP in platelets (2). As the mechanisms that underlie P2Y 12 receptor recycling remain largely unknown, we sought to define the endocytic traffic route of this receptor and identify key proteins that regulate this process.Bioinformatic analysis of the protein sequences of an array of GPCR families including the β 1 AR and β 2 AR subtypes, chemokine CXCR2, ET A endothelin receptor, P2Y 1 and P2Y 12 has revealed the presence of C-terminal type I, type ...

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SNX27, a protein involved in down syndrome, regulates GPR17 trafficking and oligodendrocyte differentiation

Meraviglia

Ulivi

Boccazzi

et al. 2016

Glia

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The G protein-coupled receptor 17 (GPR17) plays crucial roles in myelination. It is highly expressed during transition of oligodendrocyte progenitor cells to immature oligodendrocytes, but, after this stage, it must be down-regulated to allow generation of mature myelinating cells. After endocytosis, GPR17 is sorted into lysosomes for degradation or recycled to the plasma membrane. Balance between degradation and recycling is important for modulation of receptor levels at the cell surface and thus for the silencing/activation of GPR17-signaling pathways that, in turn, affect oligodendrocyte differentiation. The molecular mechanisms at the basis of these processes are still partially unknown and their characterization will allow a better understanding of myelination and provide cues to interpret the consequences of GPR17 dysfunction in diseases. Here, we demonstrate that the endocytic trafficking of GPR17 is mediated by the interaction of a type I PDZ-binding motif located at the C-terminus of the receptor and SNX27, a recently identified protein of the endosome-associated retromer complex and whose functions in oligodendrocytes have never been studied. SNX27 knock-down significantly reduces GPR17 plasma membrane recycling in differentiating oligodendrocytes while accelerating cells' terminal maturation. Interestingly, trisomy-linked down-regulation of SNX27 expression in the brain of Ts65Dn mice, a model of Down syndrome, correlates with a decrease in GPR17(+) cells and an increase in mature oligodendrocytes, which, however, fail in reaching full maturation, eventually leading to hypomyelination. Our data demonstrate that SNX27 modulates GPR17 plasma membrane recycling and stability, and that disruption of the SNX27/GPR17 interaction might contribute to pathological oligodendrocyte differentiation defects. GLIA 2016. GLIA 2016;64:1437-1460.

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Arrestin Scaffolds NHERF1 to the P2Y12 Receptor to Regulate Receptor Internalization

Cited by 32 publications

References 39 publications

PDZ Protein Regulation of G Protein–Coupled Receptor Trafficking and Signaling Pathways

PDZ Protein Regulation of G Protein–Coupled Receptor Trafficking and Signaling Pathways

Differential Endosomal Sorting of a Novel P2Y₁₂ Purinoreceptor Mutant

SNX27, a protein involved in down syndrome, regulates GPR17 trafficking and oligodendrocyte differentiation

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Arrestin Scaffolds NHERF1 to the P2Y12 Receptor to Regulate Receptor Internalization

Cited by 32 publications

References 39 publications

PDZ Protein Regulation of G Protein–Coupled Receptor Trafficking and Signaling Pathways

PDZ Protein Regulation of G Protein–Coupled Receptor Trafficking and Signaling Pathways

Differential Endosomal Sorting of a Novel P2Y12 Purinoreceptor Mutant

SNX27, a protein involved in down syndrome, regulates GPR17 trafficking and oligodendrocyte differentiation

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Differential Endosomal Sorting of a Novel P2Y₁₂ Purinoreceptor Mutant