Evolving View of Membrane Trafficking and Signaling Systems for G Protein-Coupled Receptors

  • Silvia Sposini
  • Aylin C. HanyalogluEmail author
Part of the Progress in Molecular and Subcellular Biology book series (PMSB, volume 57)


The G protein-coupled receptor (GPCR) superfamily activates complex signal pathways, yet untangling these signaling systems to understand how specificity in receptor signaling pathways is achieved, has been a challenging question. The roles of membrane trafficking in GPCR signal regulation has undergone a recent paradigm shift, from a mechanism that programs the plasma membrane G protein signaling profile to providing distinct signaling platforms critical for specifying receptor function in vivo. In this chapter, we discuss this evolution of our understanding in the endocytic trafficking systems employed by GPCRs, and how such systems play a deeply integrated role with signaling. We describe recent studies that suggest that the endomembrane compartment can provide a mechanism to both specify, and yet also diversify, GPCR signal transduction. These new evolving models could aid mechanistic understanding of complex disease and provide novel therapeutic avenues.



Actin-interacting protein 1


Protein kinase B


ALG-interacting protein X


Associated molecule with the SH3 domain of STAM


Adaptor protein 2


Adaptor protein containing PH domain, PTB domain, and leucine zipper motif


Arresting domain containing


Beta adrenergic receptor 1 or 2


Cannabinoid receptor 1


Clathrin-coated pit


Chemokine receptor 4


δ-opioid receptor


Early endosome


Epidermal growth factor


EGF receptor

EPB 50

ERM-binding phosphoprotein 50




Endosomal sorting complex required for transport


GTPase-activating protein


GPCR-associated sorting protein-1


Guanosine diphosphate


GDP exchange factor


Gαi-interacting protein C-terminus


G protein-coupled receptors


GPCR kinase


Glycogen synthase kinase 3


Guanosine triphosphate


Hepatocyte growth factor


HGF-regulated tyrosine kinase substrate


Luteinizing hormone receptor


μ-opioid receptor


Multivesicular body


Protease-activated receptor


Post-synaptic density 95/disk large/zonula occludens-1


Phosphatidylinositol-3 phosphate


Protein kinase A


Protein kinase C


Post-synaptic density protein 95


Parathyroid hormone receptor


Regulator of G protein signaling


Sorting nexin 27


Signal-transducing adaptor protein


Signal transducer and activator of transcription


TGF-beta-activated kinase 1-binding protein


Trans-Golgi network




Thyroid-stimulating hormone receptor


Ubiquitin-binding domain


Ubiquitin-specific processing protease Y


V2 vasopressin receptor


Vasodilator-stimulated phosphoprotein


Very early endosome


Vacuolar protein sorting


Wiskott–Aldrich syndrome protein and SCAR homolog


Wingless-related integration site



This work was supported by grants from the Wellcome Trust (WT085099MA), Genesis Research Trust (P15844) to A.C.H, and an Imperial College London President’s Scholarship to S.S.


  1. Abdullah N, Beg M, Soares D, Dittman JS, McGraw TE (2016) Downregulation of a GPCR by β-arrestin2-mediated switch from an endosomal to a TGN recycling pathway. Cell Rep 17(11):2966–2978. Scholar
  2. Arakaki AKS, Pan WA, Lin H, Trejo J (2018) The α-arrestin ARRDC3 suppresses breast carcinoma invasion by regulating G protein-coupled receptor lysosomal sorting and signaling. J Biol Chem 293(9):3350–3362. Scholar
  3. Barki-Harrington L, Rockman HA (2008) β-Arrestins: multifunctional cellular mediators. Physiology 23:17–22. Scholar
  4. Bianco SD, Vandepas L, Correa-Medina M, Gereben B, Mukherjee A, Kuohung W, Carroll R, Teles MG, Latronico AC, Kaiser UB (2011) KISS1R intracellular trafficking and degradation: effect of the Arg386Pro disease-associated mutation. Endocrinology 152(4):1616–1626. Scholar
  5. Birnbaumer L (2007) The discovery of signal transduction by G proteins: a personal account and an overview of the initial findings and contributions that led to our present understanding. Biochim Biophys Acta 1768(4):756–771. Scholar
  6. Boucrot E, Ferreira AP, Almeida-Souza L, Debard S, Vallis Y, Howard G, Bertot L, Sauvonnet N, McMahon HT (2015) Endophilin marks and controls a clathrin-independent endocytic pathway. Nature 517(7535):460–465. Scholar
  7. Bowman SL, Shiwarski DJ, Puthenveedu MA (2016) Distinct G protein-coupled receptor recycling pathways allow spatial control of downstream G protein signaling. J Cell Biol 214(7):797–806. Scholar
  8. Cadigan KM (2010) Receptor endocytosis: frizzled joins the ubiquitin club. EMBO J 29(13):2099–2100. Scholar
  9. Calebiro D, Nikolaev VO, Gagliani MC, de Filippis T, Dees C, Tacchetti C, Persani L, Lohse MJ (2009) Persistent cAMP-signals triggered by internalized G-protein-coupled receptors. PLoS Biol 7(8):e1000172. Scholar
  10. Cao TT, Deacon HW, Reczek D, Bretscher A, von Zastrow M (1999) A kinase-regulated PDZ-domain interaction controls endocytic sorting of the β2-adrenergic receptor. Nature 401(6750):286–290. Scholar
  11. Charfi I, Abdallah K, Gendron L, Pineyro G (2018) Delta opioid receptors recycle to the membrane after sorting to the degradation path. Cell Mol Life Sci: CMLS 75(12):2257–2271. Scholar
  12. Cho DI, Zheng M, Min C, Kwon KJ, Shin CY, Choi HK, Kim KM (2013) ARF6 and GASP-1 are post-endocytic sorting proteins selectively involved in the intracellular trafficking of dopamine D(2) receptors mediated by GRK and PKC in transfected cells. Br J Pharmacol 168(6):1355–1374. Scholar
  13. Coke CJ, Scarlett KA, Chetram MA, Jones KJ, Sandifer BJ, Davis AS, Marcus AI, Hinton CV (2016) Simultaneous activation of induced heterodimerization between CXCR4 chemokine receptor and cannabinoid receptor 2 (CB2) reveals a mechanism for regulation of tumor progression. J Biol Chem 291(19):9991–10005. Scholar
  14. Delgado-Peraza F, Ahn KH, Nogueras-Ortiz C, Mungrue IN, Mackie K, Kendall DA, Yudowski GA (2016) Mechanisms of biased β-arrestin-mediated signaling downstream from the cannabinoid 1 receptor. Mol Pharmacol 89(6):618–629. Scholar
  15. DeWire SM, Yamashita DS, Rominger DH, Liu G, Cowan CL, Graczyk TM, Chen XT, Pitis PM, Gotchev D, Yuan C, Koblish M, Lark MW, Violin JD (2013) A G protein-biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J Pharmacol Exp Ther 344(3):708–717. Scholar
  16. Dobrowolski R, Vick P, Ploper D, Gumper I, Snitkin H, Sabatini DD, De Robertis EM (2012) Presenilin deficiency or lysosomal inhibition enhances Wnt signaling through relocalization of GSK3 to the late-endosomal compartment. Cell Rep 2(5):1316–1328. Scholar
  17. Dores MR, Trejo J (2015) GPCR sorting at multivesicular endosomes. Methods Cell Biol 130:319–332. Scholar
  18. Dores MR, Chen B, Lin H, Soh UJ, Paing MM, Montagne WA, Meerloo T, Trejo J (2012a) ALIX binds a YPX(3)L motif of the GPCR PAR1 and mediates ubiquitin-independent ESCRT-III/MVB sorting. J Cell Biol 197(3):407–419. Scholar
  19. Dores MR, Paing MM, Lin H, Montagne WA, Marchese A, Trejo J (2012b) AP-3 regulates PAR1 ubiquitin-independent MVB/lysosomal sorting via an ALIX-mediated pathway. Mol Biol Cell 23(18):3612–3623. Scholar
  20. Dores MR, Lin H, Grimsey NJ, Mendez F, Trejo J (2015) The α-arrestin ARRDC3 mediates ALIX ubiquitination and G protein-coupled receptor lysosomal sorting. Mol Biol Cell 26(25):4660–4673. Scholar
  21. Dunn HA, Ferguson SS (2015) PDZ protein regulation of G protein-coupled receptor trafficking and signaling pathways. Mol Pharmacol 88(4):624–639. Scholar
  22. Eichel K, Jullie D, von Zastrow M (2016) β-Arrestin drives MAP kinase signaling from clathrin-coated structures after GPCR dissociation. Nat Cell Biol 18(3):303–310. Scholar
  23. Eichel K, Jullie D, Barsi-Rhyne B, Latorraca NR, Masureel M, Sibarita JB, Dror RO, von Zastrow M (2018) Catalytic activation of β-arrestin by GPCRs. Nature. Scholar
  24. Feinstein TN, Wehbi VL, Ardura JA, Wheeler DS, Ferrandon S, Gardella TJ, Vilardaga JP (2011) Retromer terminates the generation of cAMP by internalized PTH receptors. Nat Chem Biol 7(5):278–284. Scholar
  25. Feinstein TN, Yui N, Webber MJ, Wehbi VL, Stevenson HP, King JD Jr, Hallows KR, Brown D, Bouley R, Vilardaga JP (2013) Noncanonical control of vasopressin receptor type 2 signaling by retromer and arrestin. J Biol Chem 288(39):27849–27860. Scholar
  26. Feng X, Zhang M, Guan R, Segaloff DL (2013) Heterodimerization between the lutropin and follitropin receptors is associated with an attenuation of hormone-dependent signaling. Endocrinology 154(10):3925–3930. Scholar
  27. Ferrandon S, Feinstein TN, Castro M, Wang B, Bouley R, Potts JT, Gardella TJ, Vilardaga JP (2009) Sustained cyclic AMP production by parathyroid hormone receptor endocytosis. Nat Chem Biol 5(10):734–742. Scholar
  28. Ferre S, Casado V, Devi LA, Filizola M, Jockers R, Lohse MJ, Milligan G, Pin JP, Guitart X (2014) G protein-coupled receptor oligomerization revisited: functional and pharmacological perspectives. Pharmacol Rev 66(2):413–434. Scholar
  29. Flinn RJ, Backer JM (2010) mTORC1 signals from late endosomes: taking a TOR of the endocytic system. Cell Cycle 9(10):1869–1870. Scholar
  30. Flores-Otero J, Ahn KH, Delgado-Peraza F, Mackie K, Kendall DA, Yudowski GA (2014) Ligand-specific endocytic dwell times control functional selectivity of the cannabinoid receptor 1. Nature Commun 5:4589. Scholar
  31. Fredriksson R, Lagerstrom MC, Lundin LG, Schioth HB (2003) The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol 63(6):1256–1272. Scholar
  32. Gage RM, Kim KA, Cao TT, von Zastrow M (2001) A transplantable sorting signal that is sufficient to mediate rapid recycling of G protein-coupled receptors. J Biol Chem 276(48):44712–44720. Scholar
  33. Galet C, Min L, Narayanan R, Kishi M, Weigel NL, Ascoli M (2003) Identification of a transferable two-amino-acid motif (GT) present in the C-terminal tail of the human lutropin receptor that redirects internalized G protein-coupled receptors from a degradation to a recycling pathway. Mol Endocrinol 17(3):411–422. Scholar
  34. Galet C, Hirakawa T, Ascoli M (2004) The postendocytotic trafficking of the human lutropin receptor is mediated by a transferable motif consisting of the C-terminal cysteine and an upstream leucine. Mol Endocrinol 18(2):434–446. Scholar
  35. Gidon A, Al-Bataineh MM, Jean-Alphonse FG, Stevenson HP, Watanabe T, Louet C, Khatri A, Calero G, Pastor-Soler NM, Gardella TJ, Vilardaga JP (2014) Endosomal GPCR signaling turned off by negative feedback actions of PKA and v-ATPase. Nat Chem Biol 10(9):707–709. Scholar
  36. Girnita L, Shenoy SK, Sehat B, Vasilcanu R, Girnita A, Lefkowitz RJ, Larsson O (2005) β-Arrestin is crucial for ubiquitination and down-regulation of the insulin-like growth factor-1 receptor by acting as adaptor for the MDM2 E3 ligase. J Biol Chem 280(26):24412–24419. Scholar
  37. Gomes I, Ayoub MA, Fujita W, Jaeger WC, Pfleger KD, Devi LA (2016) G protein-coupled receptor heteromers. Annu Rev Pharmacol Toxicol 56:403–425. Scholar
  38. Gorvin CM, Rogers A, Hastoy B, Tarasov AI, Frost M, Sposini S, Inoue A, Whyte MP, Rorsman P, Hanyaloglu AC, Breitwieser GE, Thakker RV (2018) AP2? Mutations impair calcium-sensing receptor trafficking and signaling, and show an endosomal pathway to spatially direct G-protein selectivity. Cell Rep 22(4):1054–1066. Scholar
  39. Grundmann M, Merten N, Malfacini D, Inoue A, Preis P, Simon K, Ruttiger N, Ziegler N, Benkel T, Schmitt NK, Ishida S, Muller I, Reher R, Kawakami K, Inoue A, Rick U, Kuhl T, Imhof D, Aoki J, Konig GM, Hoffmann C, Gomeza J, Wess J, Kostenis E (2018) Lack of β-arrestin signaling in the absence of active G proteins. Nature Commun 9(1):341. Scholar
  40. Guo W, Urizar E, Kralikova M, Mobarec JC, Shi L, Filizola M, Javitch JA (2008) Dopamine D2 receptors form higher order oligomers at physiological expression levels. EMBO J 27(17):2293–2304. Scholar
  41. Hanyaloglu AC (2018) Advances in Membrane Trafficking and Endosomal Signaling of G Protein-Coupled Receptors. Int Rev Cell Mol Biol 339:93–131. Scholar
  42. Hanyaloglu AC, von Zastrow M (2007) A novel sorting sequence in the β2-adrenergic receptor switches recycling from default to the Hrs-dependent mechanism. J Biol Chem 282(5):3095–3104. Scholar
  43. Hanyaloglu AC, von Zastrow M (2008) Regulation of GPCRs by endocytic membrane trafficking and its potential implications. Annu Rev Pharmacol Toxicol 48:537–568. Scholar
  44. Hanyaloglu AC, McCullagh E, von Zastrow M (2005) Essential role of Hrs in a recycling mechanism mediating functional resensitization of cell signaling. EMBO J 24(13):2265–2283. Scholar
  45. Hanyu R, Wehbi VL, Hayata T, Moriya S, Feinstein TN, Ezura Y, Nagao M, Saita Y, Hemmi H, Notomi T, Nakamoto T, Schipani E, Takeda S, Kaneko K, Kurosawa H, Karsenty G, Kronenberg HM, Vilardaga JP, Noda M (2012) Anabolic action of parathyroid hormone regulated by the β2-adrenergic receptor. Proc Natl Acad Sci USA 109(19):7433–7438. Scholar
  46. Hasdemir B, Bunnett NW, Cottrell GS (2007) Hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) mediates post-endocytic trafficking of protease-activated receptor 2 and calcitonin receptor-like receptor. J Biol Chem 282(40):29646–29657. Scholar
  47. He J, Bellini M, Inuzuka H, Xu J, Xiong Y, Yang X, Castleberry AM, Hall RA (2006) Proteomic analysis of β1-adrenergic receptor interactions with PDZ scaffold proteins. J Biol Chem 281(5):2820–2827. Scholar
  48. He C, Wei Y, Sun K, Li B, Dong X, Zou Z, Liu Y, Kinch LN, Khan S, Sinha S, Xavier RJ, Grishin NV, Xiao G, Eskelinen EL, Scherer PE, Whistler JL, Levine B (2013) Beclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism. Cell 154(5):1085–1099. Scholar
  49. Henne WM, Stenmark H, Emr SD (2013) Molecular mechanisms of the membrane sculpting ESCRT pathway. Cold Spring Harb Perspect Biol 5(9).
  50. Henry AG, White IJ, Marsh M, von Zastrow M, Hislop JN (2011) The role of ubiquitination in lysosomal trafficking of delta-opioid receptors. Traffic 12(2):170–184. Scholar
  51. Henry AG, Hislop JN, Grove J, Thorn K, Marsh M, von Zastrow M (2012) Regulation of endocytic clathrin dynamics by cargo ubiquitination. Dev Cell 23(3):519–532. Scholar
  52. Hirakawa T, Galet C, Kishi M, Ascoli M (2003a) GIPC binds to the human lutropin receptor (hLHR) through an unusual PDZ domain binding motif, and it regulates the sorting of the internalized human choriogonadotropin and the density of cell surface hLHR. J Biol Chem 278(49):49348–49357. Scholar
  53. Hirakawa T, Galet C, Kishi M, Ascoli M (2003b) GIPC binds to the human lutropin receptor (hLHR) through an unusual PDZ domain binding motif, and it regulates the sorting of the internalized human choriogonadotropin and the density of cell surface hLHR. J Biol Chem 278(49):49348–49357. Scholar
  54. Hislop JN, Henry AG, Marchese A, von Zastrow M (2009) Ubiquitination regulates proteolytic processing of G protein-coupled receptors after their sorting to lysosomes. J Biol Chem 284(29):19361–19370. Scholar
  55. Hislop JN, Henry AG, von Zastrow M (2011) Ubiquitination in the first cytoplasmic loop of μ-opioid receptors reveals a hierarchical mechanism of lysosomal down-regulation. J Biol Chem 286(46):40193–40204. Scholar
  56. Huang SH, Zhao L, Sun ZP, Li XZ, Geng Z, Zhang KD, Chao MV, Chen ZY (2009) Essential role of Hrs in endocytic recycling of full-length TrkB receptor but not its isoform TrkB.T1. J Biol Chem 284(22):15126–15136. Scholar
  57. Insel PA, Wilderman A, Zambon AC, Snead AN, Murray F, Aroonsakool N, McDonald DS, Zhou S, McCann T, Zhang L, Sriram K, Chinn AM, Michkov AV, Lynch RM, Overland AC, Corriden R (2015) G protein-coupled receptor (GPCR) expression in native cells: “novel” endoGPCRs as physiologic regulators and therapeutic targets. Mol Pharmacol 88(1):181–187. Scholar
  58. Irannejad R, Tomshine JC, Tomshine JR, Chevalier M, Mahoney JP, Steyaert J, Rasmussen SG, Sunahara RK, El-Samad H, Huang B, von Zastrow M (2013) Conformational biosensors reveal GPCR signaling from endosomes. Nature 495(7442):534–538. Scholar
  59. Jean-Alphonse FG, Bowersox S, Chen S, Beard G, Puthenveedu MA, Hanyaloglu AC (2014) Spatially restricted G protein-coupled receptor activity via divergent endocytic compartments. J Biol Chem 289(7):3960–3977. Scholar
  60. Jean-Alphonse FG, Wehbi VL, Chen J, Noda M, Taboas JM, Xiao K, Vilardaga J-P (2016) β2-adrenergic receptor control of endosomal PTH receptor signaling via Gβγ. Nat Chem Biol. Scholar
  61. Jensen DD, Lieu T, Halls ML, Veldhuis NA, Imlach WL, Mai QN, Poole DP, Quach T, Aurelio L, Conner J, Herenbrink CK, Barlow N, Simpson JS, Scanlon MJ, Graham B, McCluskey A, Robinson PJ, Escriou V, Nassini R, Materazzi S, Geppetti P, Hicks GA, Christie MJ, Porter CJH, Canals M, Bunnett NW (2017) Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief. Sci Transl Med 9(392).
  62. Ji B, Liu H, Zhang R, Jiang Y, Wang C, Li S, Chen J, Bai B (2017) Novel signalling of dynorphin at κ-opioid receptor/bradykinin B2 receptor heterodimers. Cell Signal 31:66–78. Scholar
  63. Jonas KC, Fanelli F, Huhtaniemi IT, Hanyaloglu AC (2015) Single molecule analysis of functionally asymmetric G protein-coupled receptor (GPCR) oligomers reveals diverse spatial and structural assemblies. J Biol Chem 290(7):3875–3892. Scholar
  64. Kennedy JE, Marchese A (2015) Regulation of GPCR trafficking by ubiquitin. Prog Mol Biol Transl Sci 132:15–38. Scholar
  65. Kuna RS, Girada SB, Asalla S, Vallentyne J, Maddika S, Patterson JT, Smiley DL, DiMarchi RD, Mitra P (2013) Glucagon-like peptide-1 receptor-mediated endosomal cAMP generation promotes glucose-stimulated insulin secretion in pancreatic β-cells. Am J Physiol Endocrinol Metab 305(2):161–170. Scholar
  66. Lakadamyali M, Rust MJ, Zhuang X (2006) Ligands for clathrin-mediated endocytosis are differentially sorted into distinct populations of early endosomes. Cell 124(5):997–1009. Scholar
  67. Lally CC, Bauer B, Selent J, Sommer ME (2017) C-edge loops of arrestin function as a membrane anchor. Nature Commun 8:14258. Scholar
  68. Lauffer BE, Melero C, Temkin P, Lei C, Hong W, Kortemme T, von Zastrow M (2010) SNX27 mediates PDZ-directed sorting from endosomes to the plasma membrane. J Cell Biol 190(4):565–574. Scholar
  69. Lu A, Tebar F, Alvarez-Moya B, Lopez-Alcala C, Calvo M, Enrich C, Agell N, Nakamura T, Matsuda M, Bachs O (2009) A clathrin-dependent pathway leads to KRas signaling on late endosomes en route to lysosomes. J Cell Biol 184(6):863–879. Scholar
  70. Luttrell LM, Lefkowitz RJ (2002) The role of β-arrestins in the termination and transduction of G-protein-coupled receptor signals. J Cell Sci 115(Pt 3):455–465PubMedGoogle Scholar
  71. Luttrell LM, Ferguson SS, Daaka Y, Miller WE, Maudsley S, Della Rocca GJ, Lin F, Kawakatsu H, Owada K, Luttrell DK, Caron MG, Lefkowitz RJ (1999) β-Arrestin-dependent formation of β2 adrenergic receptor-Src protein kinase complexes. Science 283(5402):655–661CrossRefPubMedGoogle Scholar
  72. Lyga S, Volpe S, Werthmann RC, Gotz K, Sungkaworn T, Lohse MJ, Calebiro D (2016) Persistent cAMP signaling by internalized LH receptors in ovarian follicles. Endocrinology 157(4):1613–1621. Scholar
  73. Marchese A, Paing MM, Temple BR, Trejo J (2008) G protein-coupled receptor sorting to endosomes and lysosomes. Annu Rev Pharmacol Toxicol 48:601–629. Scholar
  74. McArdle CA, Franklin J, Green L, Hislop JN (2002) The gonadotrophin-releasing hormone receptor: signalling, cycling and desensitisation. Arch Physiol Biochem 110(1–2):113–122. Scholar
  75. McGarvey JC, Xiao K, Bowman SL, Mamonova T, Zhang Q, Bisello A, Sneddon WB, Ardura JA, Jean-Alphonse F, Vilardaga JP, Puthenveedu MA, Friedman PA (2016) Actin-sorting nexin 27 (SNX27)-retromer complex mediates rapid parathyroid hormone receptor recycling. J Biol Chem 291(21):10986–11002. Scholar
  76. Merriam LA, Baran CN, Girard BM, Hardwick JC, May V, Parsons RL (2013) Pituitary adenylate cyclase 1 receptor internalization and endosomal signaling mediate the pituitary adenylate cyclase activating polypeptide-induced increase in guinea pig cardiac neuron excitability. J Neurosci: Official J Soc Neurosci 33(10):4614–4622. Scholar
  77. Min L, Soltis K, Reis AC, Xu S, Kuohung W, Jain M, Carroll RS, Kaiser UB (2014) Dynamic kisspeptin receptor trafficking modulates kisspeptin-mediated calcium signaling. Mol Endocrinol 28(1):16–27. Scholar
  78. Moore CA, Milano SK, Benovic JL (2007) Regulation of receptor trafficking by GRKs and arrestins. Annu Rev Physiol 69:451–482. Scholar
  79. Mosser VA, Jones KT, Hoffman KM, McCarty NA, Jackson DA (2008) Differential role of β-arrestin ubiquitination in agonist-promoted down-regulation of M1 vs M2 muscarinic acetylcholine receptors. J Mol Signaling 3:20. Scholar
  80. Mukai A, Yamamoto-Hino M, Awano W, Watanabe W, Komada M, Goto S (2010) Balanced ubiquitylation and deubiquitylation of Frizzled regulate cellular responsiveness to Wg/Wnt. EMBO J 29(13):2114–2125. Scholar
  81. Mundell SJ, Luo J, Benovic JL, Conley PB, Poole AW (2006) Distinct clathrin-coated pits sort different G protein-coupled receptor cargo. Traffic 7(10):1420–1431. Scholar
  82. Musheshe N, Schmidt M, Zaccolo M (2018) cAMP: From long-range second messenger to nanodomain signalling. Trends Pharmacol Sci 39(2):209–222. Scholar
  83. Nakamura K, Liu X, Ascoli M (2000) Seven non-contiguous intracellular residues of the lutropin/choriogonadotropin receptor dictate the rate of agonist-induced internalization and its sensitivity to non-visual arrestins. J Biol Chem 275(1):241–247CrossRefPubMedGoogle Scholar
  84. Nooh MM, Bahouth SW (2017) Two barcodes encoded by the type-1 PDZ and by phospho-Ser312 regulate retromer/WASH-mediated sorting of the ss1-adrenergic receptor from endosomes to the plasma membrane. Cell Signal 29:192–208. Scholar
  85. Nooh MM, Mancarella S, Bahouth SW (2016) Identification of novel transplantable GPCR recycling motif for drug discovery. Biochem Pharmacol 120:22–32. Scholar
  86. Okazaki M, Ferrandon S, Vilardaga JP, Bouxsein ML, Potts JT Jr, Gardella TJ (2008) Prolonged signaling at the parathyroid hormone receptor by peptide ligands targeted to a specific receptor conformation. Proc Natl Acad Sci USA 105(43):16525–16530. Scholar
  87. Paing MM, Stutts AB, Kohout TA, Lefkowitz RJ, Trejo J (2002) β-Arrestins regulate protease-activated receptor-1 desensitization but not internalization or Down-regulation. J Biol Chem 277(2):1292–1300. Scholar
  88. Pardon E, Laeremans T, Triest S, Rasmussen SG, Wohlkonig A, Ruf A, Muyldermans S, Hol WG, Kobilka BK, Steyaert J (2014) A general protocol for the generation of nanobodies for structural biology. Nat Protoc 9(3):674–693. Scholar
  89. Pierce KL, Lefkowitz RJ (2001) Classical and new roles of β-arrestins in the regulation of G-protein-coupled receptors. Nat Rev Neurosci 2(10):727–733. Scholar
  90. Puthenveedu MA, von Zastrow M (2006) Cargo regulates clathrin-coated pit dynamics. Cell 127(1):113–124. Scholar
  91. Puthenveedu MA, Lauffer B, Temkin P, Vistein R, Carlton P, Thorn K, Taunton J, Weiner OD, Parton RG, Von Mark Z (2010) Sequence-dependent sorting of recycling proteins by actin-stabilized endosomal microdomains. Cell 143(5):761–773. Scholar
  92. Rankovic Z, Brust TF, Bohn LM (2016) Biased agonism: an emerging paradigm in GPCR drug discovery. Bioorg Med Chem Lett 26(2):241–250. Scholar
  93. Reiter E, Ahn S, Shukla A, Lefkowitz R (2012) Molecular mechanism of β-arrestin-biased agonism at seven-transmembrane receptors. Annual Rev Pharmacol Toxicol 52:179–276.
  94. Roman-Vendrell C, Yu YJ, Yudowski GA (2012) Fast modulation of μ-opioid receptor (MOR) recycling is mediated by receptor agonists. J Biol Chem 287(18):14782–14791. Scholar
  95. Rosciglione S, Theriault C, Boily MO, Paquette M, Lavoie C (2014) Gαs regulates the post-endocytic sorting of G protein-coupled receptors. Nature Commun 5:4556. Scholar
  96. Rusten TE, Vaccari T, Stenmark H (2011) Shaping development with ESCRTs. Nat Cell Biol 14(1):38–45. Scholar
  97. Shenoy SK (2014) Arrestin interaction with E3 ubiquitin ligases and deubiquitinases: functional and therapeutic implications. Handb Exp Pharmacol 219:187–203. Scholar
  98. Shenoy SK, Modi AS, Shukla AK, Xiao K, Berthouze M, Ahn S, Wilkinson KD, Miller WE, Lefkowitz RJ (2009) Β-arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2. Proc Natl Acad Sci USA 106(16):6650–6655. Scholar
  99. Soergel DG, Subach RA, Cowan CL, Violin JD, Lark MW (2013) First clinical experience with TRV027: pharmacokinetics and pharmacodynamics in healthy volunteers. J Clin Pharmacol 53(9):892–899. Scholar
  100. Sposini S, Jean-Alphonse FG, Ayoub MA, Oqua A, West C, Lavery S, Brosens JJ, Reiter E, Hanyaloglu AC (2017) Integration of GPCR signaling and sorting from very early endosomes via opposing APPL1 mechanisms. Cell Rep 21(10):2855–2867. Scholar
  101. Stallaert W, Christopoulos A, Bouvier M (2011) Ligand functional selectivity and quantitative pharmacology at G protein-coupled receptors. Expert Opin Drug Discov 6(8):811–825. Scholar
  102. Stevens RC, Cherezov V, Katritch V, Abagyan R, Kuhn P, Rosen H, Wuthrich K (2013) The GPCR network: a large-scale collaboration to determine human GPCR structure and function. Nat Rev Drug Discov 12(1):25–34. Scholar
  103. Stoeber M, Jullie D, Lobingier BT, Laeremans T, Steyaert J, Schiller PW, Manglik A, von Zastrow M (2018) A genetically encoded biosensor reveals location bias of opioid drug action. Neuron. Scholar
  104. Taelman VF, Dobrowolski R, Plouhinec JL, Fuentealba LC, Vorwald PP, Gumper I, Sabatini DD, De Robertis EM (2010) Wnt signaling requires sequestration of glycogen synthase kinase 3 inside multivesicular endosomes. Cell 143(7):1136–1148. Scholar
  105. Tappe-Theodor A, Agarwal N, Katona I, Rubino T, Martini L, Swiercz J, Mackie K, Monyer H, Parolaro D, Whistler J, Kuner T, Kuner R (2007) A molecular basis of analgesic tolerance to cannabinoids. J Neurosci: Official J Soc Neurosci 27(15):4165–4177. Scholar
  106. Temkin P, Lauffer B, Jager S, Cimermancic P, Krogan NJ, von Zastrow M (2011) SNX27 mediates retromer tubule entry and endosome-to-plasma membrane trafficking of signalling receptors. Nat Cell Biol 13(6):715–721. Scholar
  107. Thomsen ARB, Plouffe B, Cahill TJ, Shukla AK, Tarrasch JT, Dosey AM, Kahsai AW, Strachan RT, Pani B, Mahoney JP, Huang L, Breton B, Heydenreich FM, Sunahara RK, Skiniotis G, Bouvier M, Lefkowitz RJ (2016) GPCR-G protein-β-arrestin super-complex mediates sustained G protein signaling. Cell 166(4):907–919. Scholar
  108. Tian X, Irannejad R, Bowman SL, Du Y, Puthenveedu MA, von Zastrow M, Benovic JL (2016) The α-arrestin ARRDC3 regulates the endosomal residence time and intracellular signaling of the β2-adrenergic receptor. J Biol Chem 291(28):14510–14525. Scholar
  109. Trejo J (2005) Internal PDZ ligands: novel endocytic recycling motifs for G protein-coupled receptors. Mol Pharmacol 67(5):1388–1390. Scholar
  110. Tsvetanova NG, von Zastrow M (2014) Spatial encoding of cyclic AMP signaling specificity by GPCR endocytosis. Nat Chem Biol 10(12):1061–1065. Scholar
  111. Tsvetanova NG, Trester-Zedlitz M, Newton BW, Riordan DP, Sundaram AB, Johnson JR, Krogan NJ, von Zastrow M (2017) G protein-coupled receptor endocytosis confers uniformity in responses to chemically distinct ligands. Mol Pharmacol 91(2):145–156. Scholar
  112. Vines CM, Revankar CM, Maestas DC, LaRusch LL, Cimino DF, Kohout TA, Lefkowitz RJ, Prossnitz ER (2003) N-formyl peptide receptors internalize but do not recycle in the absence of arrestins. J Biol Chem 278(43):41581–41584. Scholar
  113. Vistein R, Puthenveedu MA (2013) Reprogramming of G protein-coupled receptor recycling and signaling by a kinase switch. Proc Natl Acad Sci USA 110(38):15289–15294. Scholar
  114. Wang J, Hanada K, Staus DP, Makara MA, Dahal GR, Chen Q, Ahles A, Engelhardt S, Rockman HA (2017) Gαi is required for carvedilol-induced β1 adrenergic receptor β-arrestin biased signaling. Nature Commun 8(1):1706. Scholar
  115. West C, Hanyaloglu AC (2015) Minireview: spatial programming of G Protein-coupled receptor activity: decoding signaling in health and disease. Mol Endocrinol 29(8):1095–1106. Scholar
  116. Xiang Y, Kobilka B (2003) The PDZ-binding motif of the β2-adrenoceptor is essential for physiologic signaling and trafficking in cardiac myocytes. Proc Natl Acad Sci USA 100(19):10776–10781. Scholar
  117. Xiao K, McClatchy DB, Shukla AK, Zhao Y, Chen M, Shenoy SK, Yates JR 3rd, Lefkowitz RJ (2007) Functional specialization of β-arrestin interactions revealed by proteomic analysis. Proc Natl Acad Sci USA 104(29):12011–12016. Scholar
  118. Xiao K, Sun J, Kim J, Rajagopal S, Zhai B, Villen J, Haas W, Kovacs JJ, Shukla AK, Hara MR, Hernandez M, Lachmann A, Zhao S, Lin Y, Cheng Y, Mizuno K, Maayan A, Gygi SP, Lefkowitz RJ (2010) Global phosphorylation analysis of β-arrestin-mediated signaling downstream of a seven transmembrane receptor (7TMR). Proc Natl Acad Sci USA 107(34):15299–15304. Scholar
  119. Yarwood RE, Imlach WL, Lieu T, Veldhuis NA, Jensen DD, Klein Herenbrink C, Aurelio L, Cai Z, Christie MJ, Poole DP, Porter CJH, McLean P, Hicks GA, Geppetti P, Halls ML, Canals M, Bunnett NW (2017) Endosomal signaling of the receptor for calcitonin gene-related peptide mediates pain transmission. Proc Natl Acad Sci USA 114(46):12309–12314. Scholar
  120. Zhang X, Sun N, Zheng M, Kim KM (2016) Clathrin-mediated endocytosis is responsible for the lysosomal degradation of dopamine D3 receptor. Biochem Biophys Res Commun 476(4):245–251. Scholar
  121. Zoncu R, Perera RM, Balkin DM, Pirruccello M, Toomre D, De Camilli P (2009) A phosphoinositide switch controls the maturation and signaling properties of APPL endosomes. Cell 136(6):1110–1121. Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institute of Reproductive and Developmental Biology, Department of Surgery and CancerHammersmith Campus, Imperial College LondonLondonUK

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