Identifying G Protein-Coupled Receptor Escorts, Chaperones, and Intracellular Tethers Regulating Receptor Density at the Cell Surface

  • Stefano Marullo
  • Liliana Pardo Lopez
  • Lamia Achour
Protocol

Abstract

G protein-coupled receptor (GPCR) responsiveness is dynamically regulated by various mechanisms, allowing fine-tuning of cell signaling. Modulation of GPCR plasma membrane density, via their release from intracellular compartments, constitutes a recently identified important process in this context. This phenomenon requires a complex network of interactions between GPCRs, “private” chaperones and escort proteins, and gatekeepers, which are directly involved in the retention of GPCRs in the intracellular compartments. The molecular and functional characterization of the players in this game is at its very beginning and requires appropriate quantitative methods of investigation to unravel the mechanisms that are involved.

Key words

GPCR Chaperone Escort protein Secretory pathway Resensitization 

References

  1. 1.
    Bockaert J, Pin JP (1999) Molecular tinkering of G protein-coupled receptors: an evolutionary success. Embo J 18:1723–1729PubMedCrossRefGoogle Scholar
  2. 2.
    Pierce KL, Premont RT, Lefkowitz RJ (2002) Seven-transmembrane receptors. Nat Rev Mol Cell Biol 3:639–650PubMedCrossRefGoogle Scholar
  3. 3.
    Ferguson SS, Barak LS, Zhang J et al (1996) G-protein-coupled receptor regulation: role of G-protein-coupled receptor kinases and arrestins. Can J Physiol Pharmacol 74:1095–1110PubMedCrossRefGoogle Scholar
  4. 4.
    Premont RT, Gainetdinov RR (2007) Physiological roles of G protein-coupled receptor kinases and arrestins. Ann Rev Physiol 69:511–534.CrossRefGoogle Scholar
  5. 5.
    Hanyaloglu AC, von Zastrow M (2008) Regulation of GPCRs by membrane trafficking and its potential implications. Ann Rev Pharmacol Toxicol 48:537–568CrossRefGoogle Scholar
  6. 6.
    Cahill CM, Morinville A, Lee MCet al (2001) Prolonged morphine treatment targets delta opioid receptors to neuronal plasma membranes and enhances delta-mediated antinociception. J Neurosci 21:7598–7607PubMedGoogle Scholar
  7. 7.
    Kim KA, von Zastrow M (2003) Neurotrophin-regulated sorting of opioid receptors in the biosynthetic pathway of neurosecretory cells. J Neurosci 23:2075–2085PubMedGoogle Scholar
  8. 8.
    Patwardhan AM, Berg KA, Akopain AN et al. (2005) Bradykinin-induced functional competence and trafficking of the delta-opioid receptor in trigeminal nociceptors J Neurosci 25:8825–8832PubMedCrossRefGoogle Scholar
  9. 9.
    Scherrer G, Imamachi N, Cao YQ et al (2009) Dissociation of the opioid receptor mechanisms that control mechanical and heat pain. Cell 137:1148–1159PubMedCrossRefGoogle Scholar
  10. 10.
    Cahill CM, Holdridge SV, Morinville A (2007) Trafficking of delta-opioid receptors and other G-protein-coupled receptors: implications for pain and analgesia. Trends Pharmacol Sci 28:23–31PubMedCrossRefGoogle Scholar
  11. 11.
    Bie B, Pan ZZ (2007) Trafficking of central opioid receptors and descending pain inhibition. Mol Pain 3:37PubMedCrossRefGoogle Scholar
  12. 12.
    Chen C, Li JG, Chen Y et al (2006) GEC1 interacts with the kappa opioid receptor and enhances expression of the receptor. J Biol Chem 281:7983–7993PubMedCrossRefGoogle Scholar
  13. 13.
    Scott L, Kruse MS, Forssberg H et al (2002) Selective up-regulation of dopamine D1 ­receptors in dendritic spines by NMDA receptor activation. Proc Natl Acad Sci USA 99:1661–1664PubMedCrossRefGoogle Scholar
  14. 14.
    Brismar H, Asghar M, Carey RM et al (1998) Dopamine-induced recruitment of dopamine D1 receptors to the plasma membrane. Proc Natl Acad Sci USA 95:5573–5578PubMedCrossRefGoogle Scholar
  15. 15.
    Holtback U, Brismar H, DiBona GF et al (1999) Receptor recruitment: a mechanism for interactions between G protein-coupled receptors. Proc Natl Acad Sci USA 96:7271–7275PubMedCrossRefGoogle Scholar
  16. 16.
    Hein L, Ishii K, Coughlin SR et al (1994) Intracellular targeting and trafficking of thrombin receptors. A novel mechanism for resensitization of a G protein-coupled receptor. J Biol Chem 269:27719–27726PubMedGoogle Scholar
  17. 17.
    Conn PM, Ulloa-Aguirre A, Ito J et al (2007) G protein-coupled receptor trafficking in health and disease: lessons learned to prepare for therapeutic mutant rescue in vivo. Pharmacol Rev 59:225–250PubMedCrossRefGoogle Scholar
  18. 18.
    Janovick JA, Knollman PE, Brothers SP et al (2006) Regulation of G protein-coupled receptor trafficking by inefficient plasma membrane expression: molecular basis of an evolved strategy. J Biol Chem 281:8417–8425PubMedCrossRefGoogle Scholar
  19. 19.
    Achour L, Scott MG, Shirvani H et al (2009) CD4 – CCR5 interaction in intracellular compartments contributes to receptor expression at the cell surface. Blood 113:1938–1947PubMedCrossRefGoogle Scholar
  20. 20.
    Ding Z, Issekutz TB, Downey GP et al (2003) L-selectin stimulation enhances functional expression of surface CXCR4 in lymphocytes: implications for cellular activation during adhesion and migration. Blood 101:4245–4252PubMedCrossRefGoogle Scholar
  21. 21.
    McLatchie LM, Fraser NJ, Main MJ et al (1998) RAMPs regulate the transport and ligand specificity of the calcitonin- receptor-like receptor. Nature 393:333–339PubMedCrossRefGoogle Scholar
  22. 22.
    Loconto J, Papes F, Chang E et al (2003) Functional expression of murine V2R pheromone receptors involves selective association with the M10 and M1 families of MHC class Ib molecules. Cell 112:607–618PubMedCrossRefGoogle Scholar
  23. 23.
    Saito H, Kubota M, Roberts RW et al (2004) RTP family members induce functional expression of mammalian odorant receptors. Cell 119:679–691PubMedCrossRefGoogle Scholar
  24. 24.
    Uberti MA, Hague C, Oller H et al (2005) Heterodimerization with beta2-adrenergic receptors promotes surface expression and functional activity of alpha1D-adrenergic receptors. J Pharmacol Exp Ther 313:16–23PubMedCrossRefGoogle Scholar
  25. 25.
    Pietila EM, Tuusa JT, Apaja PM et al (2005) Inefficient maturation of the rat luteinizing hormone receptor: A putative way to regulate receptor numbers at the cell surface. J Biol Chem 280:26622–26629PubMedCrossRefGoogle Scholar
  26. 26.
    Noon LA, Franklin JM, King PJ et al (2002) Failed export of the adrenocorticotrophin receptor from the endoplasmic reticulum in non-adrenal cells: evidence in support of a requirement for a specific adrenal accessory factor. J Endocrinol 174:17–25PubMedCrossRefGoogle Scholar
  27. 27.
    Behrens M, Bartelt J, Reichling C et al (2006) Members of RTP and REEP gene families influence functional bitter taste receptor expression. J Biol Chem 281:20650–20659PubMedCrossRefGoogle Scholar
  28. 28.
    Hebert DN, Molinari M (2007) In and out of the ER: protein folding, quality control, degradation, and related human diseases. Physiol Rev 87:1377–1408PubMedCrossRefGoogle Scholar
  29. 29.
    Achour L, Labbe-Juillie C, Scott MGH et al (2008) An escort for G Protein Coupled Receptors to find their path: implication for regulation of receptor density at the cell surface. Trends Pharmacol Sci 29:528–535PubMedCrossRefGoogle Scholar
  30. 30.
    Baker EK, Colley NJ, Zuker CS (1994) The cyclophilin homolog NinaA functions as a chaperone, forming a stable complex in vivo with its protein target rhodopsin. Embo J 13:4886–4895PubMedGoogle Scholar
  31. 31.
    Ferreira PA, Nakayama TA, Pak WL et al (1996) Cyclophilin-related protein RanBP2 acts as chaperone for red/green opsin. Nature 383:637–640PubMedCrossRefGoogle Scholar
  32. 32.
    Westhoff B, Chapple JP, van der Spuy J et al (2005) HSJ1 is a neuronal shuttling factor for the sorting of chaperone clients to the proteasome. Curr Biol 15:1058–1064PubMedCrossRefGoogle Scholar
  33. 33.
    Bermak JC, Li M, Bullock C et al (2001) Regulation of transport of the dopamine D1 receptor by a new membrane- associated ER protein. Nat Cell Biol 3:492–498.PubMedCrossRefGoogle Scholar
  34. 34.
    Leclerc PC, Auger-Messier M, Lanctot PM et al (2002) A polyaromatic caveolin-binding-like motif in the cytoplasmic tail of the type 1 receptor for angiotensin II plays an important role in receptor trafficking and signaling. Endocrinology 143:4702–4710PubMedCrossRefGoogle Scholar
  35. 35.
    Dupre DJ, Robitaille M, Richer M et al (2007) Dopamine receptor-interacting protein 78 acts as a molecular chaperone for Ggamma subunits before assembly with Gbeta. J Biol Chem 282:13703–13715PubMedCrossRefGoogle Scholar
  36. 36.
    Chen Y, Chen C, Kotsikorou E et al (2009) GEC1-kappa opioid receptor binding involves hydrophobic interactions: GEC1 has chaperone-like effect. J Biol Chem. 284:1673–1685PubMedCrossRefGoogle Scholar
  37. 37.
    Wruck CJ, Funke-Kaiser H, Pufe T et al (2005) Regulation of transport of the angiotensin AT2 receptor by a novel membrane-associated Golgi protein. Arterioscler Thromb Vasc Biol 25:57–64PubMedGoogle Scholar
  38. 38.
    Rodrigues-Ferreira S, Di Tommaso A, Dimitrov A et al (2009) 8p22 MTUS1 gene product ATIP3 is a novel anti-mitotic protein underexpressed in invasive breast carcinoma of poor prognosis. PLoS One 4:e7239PubMedCrossRefGoogle Scholar
  39. 39.
    Parent A, Laroche G, Hamelin E et al (2008) RACK1 regulates the cell surface expression of the G protein-coupled receptor for thromboxane A(2). Traffic 9:394–407PubMedCrossRefGoogle Scholar
  40. 40.
    Ikebuchi Y, Takada T, Ito Ket al (2009) Receptor for activated C-kinase 1 regulates the cellular localization and function of ABCB4. Hepatol Res. 39:1091–1107PubMedCrossRefGoogle Scholar
  41. 41.
    Dwyer ND, Troemel ER, Sengupta P et al (1998) Odorant receptor localization to olfactory cilia is mediated by ODR-4, a novel ­membrane-associated protein. Cell 93:455–466PubMedCrossRefGoogle Scholar
  42. 42.
    Cooray SN, Chan L, Webb TR et al (2009) Accessory proteins are vital for the functional expression of certain G protein-coupled receptors. Mol Cell Endocrinol 300:17–24PubMedCrossRefGoogle Scholar
  43. 43.
    Ritter SL, Hall RA (2009) Fine-tuning of GPCR activity by receptor-interacting proteins. Nat Rev Mol Cell Biol 10:819–830PubMedCrossRefGoogle Scholar
  44. 44.
    Sebag JA, Hinkle PM (2007) Melanocortin-2 receptor accessory protein MRAP forms antiparallel homodimers. Proc Natl Acad Sci USA 104:20244–20249PubMedCrossRefGoogle Scholar
  45. 45.
    Sebag JA, Hinkle PM (2009) Opposite effects of the melanocortin-2 (MC2) receptor accessory protein MRAP on MC2 and MC5 receptor dimerization and trafficking. J Biol Chem 284:22641–22648PubMedCrossRefGoogle Scholar
  46. 46.
    Metherell LA, Chapple JP, Cooray S et al (2005) Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2. Nat Genet 37:166–170PubMedCrossRefGoogle Scholar
  47. 47.
    Zuchner S, Wang G, Tran-Viet KN et al (2006) Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. Am J Hum Genet 79:365–369PubMedCrossRefGoogle Scholar
  48. 48.
    Beetz C, Schule R, Deconinck T et al (2008) REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31. Brain 131:1078–1086PubMedCrossRefGoogle Scholar
  49. 49.
    Svenningsson P, Chergui K, Rachleff I et al (2006) Alterations in 5-HT1B receptor function by p11 in depression-like states. Science 311:77–80PubMedCrossRefGoogle Scholar
  50. 50.
    Donato R (1999) Functional roles of S100 proteins, calcium-binding proteins of the EF-hand type. Biochim Biophys Acta 1450:191–231PubMedCrossRefGoogle Scholar
  51. 51.
    Doyle C, Strominger JL (1987) Interaction between CD4 and class II MHC molecules mediates cell adhesion. Nature 330:256–259PubMedCrossRefGoogle Scholar
  52. 52.
    Alkhatib G, Combadiere C, Broder CC et al (1996) CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 272:1955–1958.PubMedCrossRefGoogle Scholar
  53. 53.
    Parameswaran N, Spielman WS (2006) RAMPs: the past, present and future. Trends Biochem Sci 31:631–638PubMedCrossRefGoogle Scholar
  54. 54.
    Duvernay MT, Zhou F, Wu G (2004) A conserved motif for the transport of G protein-coupled receptors from the endoplasmic reticulum to the cell surface. J Biol Chem 279:30741–30750PubMedCrossRefGoogle Scholar
  55. 55.
    Duvernay MT, Dong C, Zhang X et al (2009) Anterograde trafficking of G protein-coupled receptors: function of the C-terminal F(X)6LL motif in export from the endoplasmic reticulum. Mol Pharmacol 75:751–761PubMedCrossRefGoogle Scholar
  56. 56.
    Sawyer GW, Ehlert FJ, Shults CA (2010) A conserved motif in the membrane proximal C-terminal tail of human muscarinic M1 acetylcholine receptors affects plasma membrane expression. J Pharmacol Exp Ther 332:76–86PubMedCrossRefGoogle Scholar
  57. 57.
    Preisser L, Ancellin N, Michaelis L et al (1999) Role of the carboxyl-terminal region, di-leucine motif and cysteine residues in signalling and internalization of vasopressin V1a receptor. FEBS Lett. 460:303–308PubMedCrossRefGoogle Scholar
  58. 58.
    Heymann JA, Subramaniam S (1997) Expression, stability, and membrane integration of truncation mutants of bovine rhodopsin. Proc Natl Acad Sci USA 94:4966–4971PubMedCrossRefGoogle Scholar
  59. 59.
    Pankevych H, Korkhov V, Freissmuth M et al (2003) Truncation of the A1 adenosine receptor reveals distinct roles of the membrane-proximal carboxyl terminus in receptor folding and G protein coupling. J Biol Chem 278:30283–30293PubMedCrossRefGoogle Scholar
  60. 60.
    Robert J, Clauser E, Petit PX et al (2005) A novel C-terminal motif is necessary for the export of the vasopressin V1b/V3 receptor to the plasma membrane. J Biol Chem 280:2300–2308PubMedCrossRefGoogle Scholar
  61. 61.
    Robert J, Auzan C, Ventura MA et al (2005) Mechanisms of cell-surface rerouting of an endoplasmic reticulum-retained mutant of the vasopressin V1b/V3 receptor by a pharmacological chaperone. J Biol Chem 280:42198–42206.PubMedCrossRefGoogle Scholar
  62. 62.
    Wang W, Loh HH, Law PY (2003) The intracellular trafficking of opioid receptors directed by carboxyl tail and a di-leucine motif in neuro2A cells. J Biol Chem 278:36848–36858PubMedCrossRefGoogle Scholar
  63. 63.
    Duvernay MT, Dong C, Zhang X et al (2009) A single conserved leucine residue on the first intracellular loop regulates ER export of G ­protein-coupled receptors. Traffic 10:552–566PubMedCrossRefGoogle Scholar
  64. 64.
    Dong C, Wu G (2006) Regulation of anterograde transport of alpha2-adrenergic receptors by the N termini at multiple intracellular compartments. J Biol Chem 281:38543–38554PubMedCrossRefGoogle Scholar
  65. 65.
    Luo W, Wang Y, Reiser G (2007) p24A, a type I transmembrane protein, controls ARF1-dependent resensitization of protease-activated receptor-2 by influence on receptor trafficking. J Biol Chem 282:30246–30255PubMedCrossRefGoogle Scholar
  66. 66.
    Yamamoto A, Nagano T, Takehara S et al (2005) Shisa promotes head formation through the inhibition of receptor protein maturation for the caudalizing factors, Wnt and FGF. Cell 120:223–235PubMedCrossRefGoogle Scholar
  67. 67.
    Couturier C, Sarkis C, Seron K et al (2007) Silencing of OB-RGRP in mouse hypothalamic arcuate nucleus increases leptin receptor signaling and prevents diet-induced obesity. Proc Natl Acad Sci USA 104:19476–19481PubMedCrossRefGoogle Scholar
  68. 68.
    Spasic D, Raemaekers T, Dillen K et al (2007) Rer1p competes with APH-1 for binding to nicastrin and regulates gamma-secretase complex assembly in the early secretory pathway. J Cell Biol 176:629–640PubMedCrossRefGoogle Scholar
  69. 69.
    Ruggiero AM, Liu Y, Vidensky S et al (2008) The endoplasmic reticulum exit of glutamate transporter is regulated by the inducible mammalian Yip6b/GTRAP3-18 protein. J Biol Chem 283:6175–6183PubMedCrossRefGoogle Scholar
  70. 70.
    Daulat AM, Maurice P, Froment C et al (2007) Purification and identification of G protein-coupled receptor protein complexes under native conditions. Mol Cell Proteomics 6:835–844PubMedCrossRefGoogle Scholar
  71. 71.
    Daulat AM, Maurice P, Jockers R (2009) Recent methodological advances in the discovery of GPCR-associated protein complexes. Trends Pharmacol Sci 30:72–78PubMedCrossRefGoogle Scholar
  72. 72.
    Boutros M, Ahringer J (2008) The art and design of genetic screens: RNA interference. Nat Rev Genet 9:554–566PubMedCrossRefGoogle Scholar
  73. 73.
    Muff R, Buhlmann N, Fischer JA et al (1999) An amylin receptor is revealed following co-transfection of a calcitonin receptor with receptor activity modifying proteins-1 or -3. Endocrinology 140:2924–2927PubMedCrossRefGoogle Scholar
  74. 74.
    Bouschet T, Martin S, Henley JM (2005) Receptor-activity-modifying proteins are required for forward trafficking of the calcium-sensing receptor to the plasma membrane. J Cell Sci 118:4709–4720PubMedCrossRefGoogle Scholar
  75. 75.
    Christopoulos A, Christopoulos G, Morfis M et al (2003) Novel receptor partners and function of receptor activity-modifying proteins. J Biol Chem 278:3293–3297PubMedCrossRefGoogle Scholar
  76. 76.
    Decaillot FM, Rozenfeld R, Gupta A et al (2008) Cell surface targeting of mu-delta opioid receptor heterodimers by RTP4. Proc Natl Acad Sci USA 105:16045–16050PubMedCrossRefGoogle Scholar
  77. 77.
    Olson R, Dulac C, Bjorkman PJ (2006) MHC homologs in the nervous system — they haven’t lost their groove. Curr Opin Neurobiol 16:351–357PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Stefano Marullo
    • 1
  • Liliana Pardo Lopez
  • Lamia Achour
  1. 1.AchourInstitut Cochin,Université Paris Descartes, CNRS-INSERMParisFranceL

Personalised recommendations