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Ligand-Selective Receptor Desensitization and Endocytosis

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Functional Selectivity of G Protein-Coupled Receptor Ligands

Part of the book series: The Receptors ((REC))

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Abstract

Following activation by its endogenous agonist ligand(s), nearly every G protein-coupled receptor (GPCR) studied to date undergoes regulation by a cascade of events that includes receptor desensitization, receptor endocytosis, receptor recycling, and/or receptor degradation. However, not all GPCR agonists promote receptor desensitization and endocytosis. Indeed, the ability of an agonist to promote endocytosis does not always vary in a linear fashion with agonist activity, and even GPCR antagonists, in some cases, can promote endocytosis, indicating that receptor desensitization and endocytosis are independent functional properties that can display ligand-selective effects, or functional selectivity. Therefore, for any GPCR-ligand pair there are at least two trafficking properties that must be assessed to fully understand signal transduction: (1) whether or not the ligand promotes endocytosis of the receptor and (2) where that receptor goes following its endocytosis. For the vast majority of drugs that target GPCRs neither of these things are known. In this chapter, we outline several cases in which ligands show functional selectivity for receptor trafficking with an emphasis on receptors in which altered ligand-induced trafficking has been shown to be relevant to human disease.

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References

  1. Ferguson SS, Zhang J, Barak LS, Caron MG. Molecular mechanisms of G protein-coupled receptor desensitization and resensitization. Life Sci 1998;62(17–18):1561–5.

    Article  PubMed  CAS  Google Scholar 

  2. Whistler JL, Chuang HH, Chu P, Jan LY, von Zastrow M. Functional dissociation of mu opioid receptor signaling and endocytosis: implications for the biology of opiate tolerance and addiction. Neuron 1999;23(4):737–46.

    Article  PubMed  CAS  Google Scholar 

  3. Alvarez VA, Arttamangkul S, Dang V, . mu-Opioid receptors: ligand-dependent activation of potassium conductance, desensitization, and internalization. J Neurosci 2002;22(13):5769–76.

    PubMed  CAS  Google Scholar 

  4. Willins DL, Berry SA, Alsayegh L, . Clozapine and other 5-hydroxytryptamine-2A receptor antagonists alter the subcellular distribution of 5-hydroxytryptamine-2A receptors in vitro and in vivo. Neuroscience 1999;91(2):599–606.

    Article  PubMed  CAS  Google Scholar 

  5. Martini L, Whistler JL. The role of mu opioid receptor desensitization and endocytosis in morphine tolerance and dependence. Curr Opin Neurobiol 2007;17(5):556–64.

    Article  PubMed  CAS  Google Scholar 

  6. Keith DE, Murray SR, Zaki PA, . Morphine activates opioid receptors without causing their rapid internalization. J Biol Chem 1996;271(32):19021–4.

    Article  PubMed  CAS  Google Scholar 

  7. Arden JR, Segredo V, Wang Z, Lameh J, Sadee W. Phosphorylation and agonist-specific intracellular trafficking of an epitope-tagged mu-opioid receptor expressed in HEK 293 cells. J Neurochem 1995;65(4):1636–45.

    Article  PubMed  CAS  Google Scholar 

  8. Koch T, Schulz S, Pfeiffer M, . C-terminal splice variants of the mouse mu-opioid receptor differ in morphine-induced internalization and receptor resensitization. J Biol Chem 2001;276(33):31408–14.

    Article  PubMed  CAS  Google Scholar 

  9. Whistler JL, von Zastrow M. Morphine-activated opioid receptors elude desensitization by beta-arrestin. Proc Natl Acad Sci USA 1998;95(17):9914–9.

    Article  PubMed  CAS  Google Scholar 

  10. Yu Y, Zhang L, Yin X, Sun H, Uhl GR, Wang JB. Mu opioid receptor phosphorylation, desensitization, and ligand efficacy. J Biol Chem 1997;272(46):28869–74.

    Article  PubMed  CAS  Google Scholar 

  11. Whistler JL, Enquist J, Marley A, . Modulation of postendocytic sorting of G protein-coupled receptors. Science 2002;297(5581):615–20.

    Article  PubMed  CAS  Google Scholar 

  12. Keith DE, Anton B, Murray SR, . mu-Opioid receptor internalization: opiate drugs have differential effects on a conserved endocytic mechanism in vitro and in the mammalian brain. Mol Pharmacol 1998;53(3):377–84.

    PubMed  CAS  Google Scholar 

  13. He L, Whistler JL. An opiate cocktail that reduces morphine tolerance and dependence. Curr Biol 2005;15(11):1028–33.

    Article  PubMed  CAS  Google Scholar 

  14. He L, Fong J, von Zastrow M, Whistler JL. Regulation of opioid receptor trafficking and morphine tolerance by receptor oligomerization. Cell 2002;108(2):271–82.

    Article  PubMed  CAS  Google Scholar 

  15. Trafton JA, Abbadie C, Marek K, Basbaum AI. Postsynaptic signaling via the [mu]-opioid receptor: responses of dorsal horn neurons to exogenous opioids and noxious stimulation. J Neurosci 2000;20(23):8578–84.

    PubMed  CAS  Google Scholar 

  16. Kovoor A, Celver JP, Wu A, Chavkin C. Agonist induced homologous desensitization of mu-opioid receptors mediated by G protein-coupled receptor kinases is dependent on agonist efficacy. Mol Pharmacol 1998;54(4):704–11.

    PubMed  CAS  Google Scholar 

  17. Selley DE, Liu Q, Childers SR. Signal transduction correlates of mu opioid agonist intrinsic efficacy: receptor-stimulated [35S]GTP gamma S binding in mMOR-CHO cells and rat thalamus. J Pharmacol Exp Ther 1998;285(2):496–505.

    PubMed  CAS  Google Scholar 

  18. Finn AK, Whistler JL. Endocytosis of the mu opioid receptor reduces tolerance and a cellular hallmark of opiate withdrawal. Neuron 2001;32(5):829–39.

    Article  PubMed  CAS  Google Scholar 

  19. Kim JA, Bartlett S, He L, . Morphine-induced receptor endocytosis in a novel knockin mouse reduces tolerance and dependence. Curr Biol 2008;18(2):129–35.

    Article  PubMed  CAS  Google Scholar 

  20. Zaki PA, Keith DE Jr., Thomas JB, Carroll FI, Evans CJ. Agonist-, antagonist-, and inverse agonist-regulated trafficking of the delta-opioid receptor correlates with, but does not require, G protein activation. J Pharmacol Exp Ther 2001;298(3):1015–20.

    PubMed  CAS  Google Scholar 

  21. Remmers AE, Clark MJ, Liu XY, Medzihradsky F. Delta opioid receptor down-regulation is independent of functional G protein yet is dependent on agonist efficacy. J Pharmacol Exp Ther 1998;287(2):625–32.

    PubMed  CAS  Google Scholar 

  22. Raynor K, Kong H, Chen Y, . Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors. Mol Pharmacol 1994;45(2):330–4.

    PubMed  CAS  Google Scholar 

  23. Von Zastrow M, Keith DE Jr., Evans CJ. Agonist-induced state of the delta-opioid receptor that discriminates between opioid peptides and opiate alkaloids. Mol Pharmacol 1993;44(1):166–72.

    PubMed  CAS  Google Scholar 

  24. Li JG, Zhang F, Jin XL, Liu-Chen LY. Differential regulation of the human kappa opioid receptor by agonists: etorphine and levorphanol reduced dynorphin A- and U50,488H-induced internalization and phosphorylation. J Pharmacol Exp Ther 2003;305(2):531–40.

    Article  PubMed  CAS  Google Scholar 

  25. Tsao PI, von Zastrow M. Type-specific sorting of G protein-coupled receptors after endocytosis. J Biol Chem 2000;275(15):11130–40.

    Article  PubMed  CAS  Google Scholar 

  26. Marie N, Lecoq I, Jauzac P, Allouche S. Differential sorting of human delta-opioid receptors after internalization by peptide and alkaloid agonists. J Biol Chem 2003;278(25):22795–804.

    Article  PubMed  CAS  Google Scholar 

  27. Audet N, Paquin-Gobeil M, Landry-Paquet O, Schiller PW, Pineyro G. Internalization and Src activity regulate the time course of ERK activation by delta opioid receptor ligands. J Biol Chem 2005;280(9):7808–16.

    Article  PubMed  CAS  Google Scholar 

  28. Gray JA, Roth BL. Paradoxical trafficking and regulation of 5-HT(2A) receptors by agonists and antagonists. Brain Res Bull 2001;56(5):441–51.

    Article  PubMed  CAS  Google Scholar 

  29. Meltzer HY. Action of atypical antipsychotics. Am J Psychiatry 2002;159(1):153–4; author reply 154–5.

    Article  PubMed  Google Scholar 

  30. Nichols DE. Hallucinogens. Pharmacol Ther 2004;101(2):131–81.

    Article  PubMed  CAS  Google Scholar 

  31. Kurrasch-Orbaugh DM, Parrish JC, Watts VJ, Nichols DE. A complex signaling cascade links the serotonin2A receptor to phospholipase A2 activation: the involvement of MAP kinases. J Neurochem 2003;86(4):980–91.

    Article  PubMed  CAS  Google Scholar 

  32. Urban JD, Clarke WP, von Zastrow M, . Functional selectivity and classical concepts of quantitative pharmacology. J Pharmacol Exp Ther 2007;320(1):1–13.

    Article  PubMed  CAS  Google Scholar 

  33. Schmid CL, Raehal KM, Bohn LM. Agonist-directed signaling of the serotonin 2A receptor depends on beta-arrestin2 interactions in vivo. Proc Natl Acad Sci USA 2008;105(3):1079–84.

    Article  PubMed  CAS  Google Scholar 

  34. Ariano MA, Sortwell CE, Ray M, Altemus KL, Sibley DR, Levine MS. Agonist-induced morphologic decrease in cellular D1A dopamine receptor staining. Synapse 1997;27(4):313–21.

    Article  PubMed  CAS  Google Scholar 

  35. Vickery RG, von Zastrow M. Distinct dynamin-dependent and -independent mechanisms target structurally homologous dopamine receptors to different endocytic membranes. J Cell Biol 1999;144(1):31–43.

    Article  PubMed  CAS  Google Scholar 

  36. Bartlett SE, Enquist J, Hopf FW, . Dopamine responsiveness is regulated by targeted sorting of D2 receptors. Proc Natl Acad Sci USA 2005;102(32):11521–6.

    Article  PubMed  CAS  Google Scholar 

  37. Paspalas CD, Rakic P, Goldman-Rakic PS. Internalization of D2 dopamine receptors is clathrin-dependent and select to dendro-axonic appositions in primate prefrontal cortex. Eur J Neurosci 2006;24(5):1395–403.

    Article  PubMed  Google Scholar 

  38. Kim KM, Valenzano KJ, Robinson SR, Yao WD, Barak LS, Caron MG. Differential regulation of the dopamine D2 and D3 receptors by G protein-coupled receptor kinases and beta-arrestins. J Biol Chem 2001;276(40):37409–14.

    Article  PubMed  CAS  Google Scholar 

  39. Cho EY, Cho DI, Park JH, Kurose H, Caron MG, Kim KM. Roles of protein kinase C and actin-binding protein 280 in the regulation of intracellular trafficking of dopamine D3 receptor. Mol Endocrinol 2007;21(9):2242–54.

    Article  PubMed  CAS  Google Scholar 

  40. Ryman-Rasmussen JP, Nichols DE, Mailman RB. Differential activation of adenylate cyclase and receptor internalization by novel dopamine D1 receptor agonists. Mol Pharmacol 2005;68(4):1039–48.

    Article  PubMed  CAS  Google Scholar 

  41. Ryman-Rasmussen JP, Griffith A, Oloff S, . Functional selectivity of dopamine D1 receptor agonists in regulating the fate of internalized receptors. Neuropharmacology 2007;52(2):562–75.

    Article  PubMed  CAS  Google Scholar 

  42. Jones SR, Gainetdinov RR, Hu XT, . Loss of autoreceptor functions in mice lacking the dopamine transporter. Nat Neurosci 1999;2(7):649–55.

    Article  PubMed  CAS  Google Scholar 

  43. Attarbaschi T, Sacher J, Geiss-Granadia T, . Striatal D(2) receptor occupancy in bipolar patients treated with olanzapine. Eur Neuropsychopharmacol 2007;17(2):102–7.

    Article  PubMed  CAS  Google Scholar 

  44. Kasper S, Tauscher J, Willeit M, . Receptor and transporter imaging studies in schizophrenia, depression, bulimia and Tourette's disorder--implications for psychopharmacology. World J Biol Psychiatry 2002;3(3):133–46.

    Article  PubMed  Google Scholar 

  45. Kasper S, Tauscher J, Kufferle B, . Sertindole and dopamine D2 receptor occupancy in comparison to risperidone, clozapine and haloperidol - a 123I-IBZM SPECT study. Psychopharmacology (Berl) 1998;136(4):367–73.

    Article  CAS  Google Scholar 

  46. Parsey RV, Oquendo MA, Zea-Ponce Y, . Dopamine D(2) receptor availability and amphetamine-induced dopamine release in unipolar depression. Biol Psychiatry 2001;50(5):313–22.

    Article  PubMed  CAS  Google Scholar 

  47. Schneier FR, Liebowitz MR, Abi-Dargham A, Zea-Ponce Y, Lin SH, Laruelle M. Low dopamine D(2) receptor binding potential in social phobia. Am J Psychiatry 2000;157(3):457–9.

    Article  PubMed  CAS  Google Scholar 

  48. Schneier FR, Martinez D, Abi-Dargham A, . Striatal dopamine D(2) receptor availability in OCD with and without comorbid social anxiety disorder: preliminary findings. Depress Anxiety 2008;25(1):1–7.

    Article  PubMed  Google Scholar 

  49. Morgan D, Grant KA, Prioleau OA, Nader SH, Kaplan JR, Nader MA. Predictors of social status in cynomolgus monkeys (Macaca fascicularis) after group formation. Am J Primatol 2000;52(3):115–31.

    Article  PubMed  CAS  Google Scholar 

  50. Morgan D, Grant KA, Gage HD, Social dominance in monkeys: dopamine D2 receptors and cocaine self-administration. Nat Neurosci 2002;5(2):169–74.

    Article  PubMed  CAS  Google Scholar 

  51. Fowler JS, Volkow ND, Kassed CA, Chang L. Imaging the addicted human brain. Sci Pract Perspect 2007;3(2):4–16.

    Article  PubMed  Google Scholar 

  52. Volkow ND, Chang L, Wang GJ, . Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex. Am J Psychiatry 2001;158(12):2015–21.

    Article  PubMed  CAS  Google Scholar 

  53. Volkow ND, Wang GJ, Maynard L, . Effects of alcohol detoxification on dopamine D2 receptors in alcoholics: a preliminary study. Psychiatry Res 2002;116(3):163–72.

    Article  PubMed  CAS  Google Scholar 

  54. Volkow ND, Fowler JS, Wang GJ. The addicted human brain: insights from imaging studies. J Clin Invest 2003;111(10):1444–51.

    PubMed  CAS  Google Scholar 

  55. Czoty PW, Morgan D, Shannon EE, Gage HD, Nader MA. Characterization of dopamine D1 and D2 receptor function in socially housed cynomolgus monkeys self-administering cocaine. Psychopharmacology (Berl) 2004;174(3):381–8.

    Article  CAS  Google Scholar 

  56. Czoty PW, Gage HD, Nader MA. PET imaging of striatal dopamine D2 receptors in nonhuman primates: increases in availability produced by chronic raclopride treatment. Synapse 2005;58(4):215–9.

    Article  PubMed  CAS  Google Scholar 

  57. Nader MA, Morgan D, Gage HD, . PET imaging of dopamine D2 receptors during chronic cocaine self-administration in monkeys. Nat Neurosci 2006;9(8):1050–6.

    Article  PubMed  CAS  Google Scholar 

  58. Moore RJ, Vinsant SL, Nader MA, Porrino LJ, Friedman DP. Effect of cocaine self-administration on dopamine D2 receptors in rhesus monkeys. Synapse 1998;30(1):88–96.

    Article  PubMed  CAS  Google Scholar 

  59. Chen JF, Aloyo VJ, Weiss B. Continuous treatment with the D2 dopamine receptor agonist quinpirole decreases D2 dopamine receptors, D2 dopamine receptor messenger RNA and proenkephalin messenger RNA, and increases mu opioid receptors in mouse striatum. Neuroscience 1993;54(3):669–80.

    Article  PubMed  CAS  Google Scholar 

  60. Subramaniam S, Lucki I, McGonigle P. Effects of chronic treatment with selective agonists on the subtypes of dopamine receptors. Brain Res 1992;571(2):313–22.

    Article  PubMed  CAS  Google Scholar 

  61. Palomo T, Archer T, Kostrzewa RM, Beninger RJ. Comorbidity of substance abuse with other psychiatric disorders. Neurotox Res 2007;12(1):17–27.

    Article  PubMed  CAS  Google Scholar 

  62. Sikich L. Efficacy of atypical antipsychotics in early-onset schizophrenia and other psychotic disorders. J Clin Psychiatry 2008;69 Suppl 4:21–5.

    PubMed  CAS  Google Scholar 

  63. Shopsin B, Gershon S. Dopamine receptor stimulation in the treatment of depression: piribedil (ET-495). Neuropsychobiology 1978;4(1):1–14.

    Article  PubMed  CAS  Google Scholar 

  64. Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A. Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes. J Pharmacol Exp Ther 2002;303(2):791–804.

    Article  PubMed  CAS  Google Scholar 

  65. Bouras N, Bridges PK. Bromocriptine in depression. Curr Med Res Opin 1982;8(3):150–3.

    Article  PubMed  CAS  Google Scholar 

  66. Mack M, Luckow B, Nelson PJ, . Aminooxypentane-RANTES induces CCR5 internalization but inhibits recycling: a novel inhibitory mechanism of HIV infectivity. J Exp Med 1998;187(8):1215–24.

    Article  PubMed  CAS  Google Scholar 

  67. Simmons G, Clapham PR, Picard L, . Potent inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist. Science 1997;276(5310):276–9.

    Article  PubMed  CAS  Google Scholar 

  68. Hsieh C, Brown S, Derleth C, Mackie K. Internalization and recycling of the CB1 cannabinoid receptor. J Neurochem 1999;73(2):493–501.

    Article  PubMed  CAS  Google Scholar 

  69. Coutts AA, Anavi-Goffer S, Ross RA, . Agonist-induced internalization and trafficking of cannabinoid CB1 receptors in hippocampal neurons. J Neurosci 2001;21(7):2425–33.

    PubMed  CAS  Google Scholar 

  70. Leterrier C, Bonnard D, Carrel D, Rossier J, Lenkei Z. Constitutive endocytic cycle of the CB1 cannabinoid receptor. J Biol Chem 2004;279(34):36013–21.

    Article  PubMed  CAS  Google Scholar 

  71. Martini L, Waldhoer M, Pusch M, . Ligand-induced down-regulation of the cannabinoid 1 receptor is mediated by the G-protein-coupled receptor-associated sorting protein GASP1. Faseb J 2007;21(3):802–11.

    Article  PubMed  CAS  Google Scholar 

  72. Leterrier C, Laine J, Darmon M, Boudin H, Rossier J, Lenkei Z. Constitutive activation drives compartment-selective endocytosis and axonal targeting of type 1 cannabinoid receptors. J Neurosci 2006;26(12):3141–53.

    Article  PubMed  CAS  Google Scholar 

  73. Sneddon WB, Magyar CE, Willick GE, . Ligand-selective dissociation of activation and internalization of the parathyroid hormone (PTH) receptor: conditional efficacy of PTH peptide fragments. Endocrinology 2004;145(6):2815–23.

    Article  PubMed  CAS  Google Scholar 

  74. Pelkey KA, Yuan X, Lavezzari G, Roche KW, McBain CJ. mGluR7 undergoes rapid internalization in response to activation by the allosteric agonist AMN082. Neuropharmacology 2007;52(1):108–17.

    Article  PubMed  CAS  Google Scholar 

  75. Enquist J, Skroder C, Whistler JL, Leeb-Lundberg LM. Kinins promote B2 receptor endocytosis and delay constitutive B1 receptor endocytosis. Mol Pharmacol 2007;71(2):494–507.

    Article  PubMed  CAS  Google Scholar 

  76. Mohammad S, Baldini G, Granell S, Narducci P, Martelli AM, Baldini G. Constitutive traffic of melanocortin-4 receptor in Neuro2A cells and immortalized hypothalamic neurons. J Biol Chem 2007;282(7):4963–74.

    Article  PubMed  CAS  Google Scholar 

  77. Lavezzari G, Roche KW. Constitutive endocytosis of the metabotropic glutamate receptor mGluR7 is clathrin-independent. Neuropharmacology 2007;52(1):100–7.

    Article  PubMed  CAS  Google Scholar 

  78. Fourgeaud L, Bessis AS, Rossignol F, Pin JP, Olivo-Marin JC, Hemar A. The metabotropic glutamate receptor mGluR5 is endocytosed by a clathrin-independent pathway. J Biol Chem 2003;278(14):12222–30.

    Article  PubMed  CAS  Google Scholar 

  79. Dale LB, Bhattacharya M, Seachrist JL, Anborgh PH, Ferguson SS. Agonist-stimulated and tonic internalization of metabotropic glutamate receptor 1a in human embryonic kidney 293 cells: agonist-stimulated endocytosis is beta-arrestin1 isoform-specific. Mol Pharmacol 2001;60(6):1243–53.

    PubMed  CAS  Google Scholar 

  80. Waldhoer M, Casarosa P, Rosenkilde MM, . The carboxyl terminus of human cytomegalovirus-encoded 7 transmembrane receptor US28 camouflages agonism by mediating constitutive endocytosis. J Biol Chem 2003;278(21):19473–82.

    Article  PubMed  CAS  Google Scholar 

  81. Whistler JL, Gerber BO, Meng EC, Baranski TJ, von Zastrow M, Bourne HR. Constitutive activation and endocytosis of the complement factor 5a receptor: evidence for multiple activated conformations of a G protein-coupled receptor. Traffic 2002;3(12):866–77.

    Article  PubMed  CAS  Google Scholar 

  82. Pin JP, Kniazeff J, Binet V, . Activation mechanism of the heterodimeric GABA(B) receptor. Biochem Pharmacol 2004;68(8):1565–72.

    Article  PubMed  CAS  Google Scholar 

  83. Kniazeff J, Bessis AS, Maurel D, Ansanay H, Prezeau L, Pin JP. Closed state of both binding domains of homodimeric mGlu receptors is required for full activity. Nat Struct Mol Biol 2004;11(8):706–13.

    Article  PubMed  CAS  Google Scholar 

  84. Nelson G, Chandrashekar J, Hoon MA, . An amino-acid taste receptor. Nature 2002;416(6877):199–202.

    Article  PubMed  CAS  Google Scholar 

  85. Filipek S, Krzysko KA, Fotiadis D, . A concept for G protein activation by G protein-coupled receptor dimers: the transducin/rhodopsin interface. Photochem Photobiol Sci 2004;3(6):628–38.

    Article  PubMed  CAS  Google Scholar 

  86. Jordan BA, Devi LA. G-protein-coupled receptor heterodimerization modulates receptor function. Nature 1999;399(6737):697–700.

    Article  PubMed  CAS  Google Scholar 

  87. George SR, Fan T, Xie Z, . Oligomerization of mu- and delta-opioid receptors. Generation of novel functional properties. J Biol Chem 2000;275(34):26128–35.

    Article  PubMed  CAS  Google Scholar 

  88. Gomes I, Gupta A, Filipovska J, Szeto HH, Pintar JE, Devi LA. A role for heterodimerization of mu and delta opiate receptors in enhancing morphine analgesia. Proc Natl Acad Sci USA 2004;101(14):5135–9.

    Article  PubMed  CAS  Google Scholar 

  89. Lee SP, O'Dowd BF, Rajaram RD, Nguyen T, George SR. D2 dopamine receptor homodimerization is mediated by multiple sites of interaction, including an intermolecular interaction involving transmembrane domain 4. Biochemistry 2003;42(37):11023–31.

    Article  PubMed  CAS  Google Scholar 

  90. Pfeiffer M, Koch T, Schroder H, Laugsch M, Hollt V, Schulz S. Heterodimerization of somatostatin and opioid receptors cross-modulates phosphorylation, internalization, and desensitization. J Biol Chem 2002;277(22):19762–72.

    Article  PubMed  CAS  Google Scholar 

  91. Mellado M, Rodriguez-Frade JM, Vila-Coro AJ, . Chemokine receptor homo- or heterodimerization activates distinct signaling pathways. Embo J 2001;20(10):2497–507.

    Article  PubMed  CAS  Google Scholar 

  92. Gomes I, Jordan BA, Gupta A, Trapaidze N, Nagy V, Devi LA. Heterodimerization of mu and delta opioid receptors: A role in opiate synergy. J Neurosci 2000;20(22):RC110.

    PubMed  CAS  Google Scholar 

  93. Maggio R, Vogel Z, Wess J. Coexpression studies with mutant muscarinic/adrenergic receptors provide evidence for intermolecular “cross-talk” between G-protein-linked receptors. Proc Natl Acad Sci USA 1993;90(7):3103–7.

    Article  PubMed  CAS  Google Scholar 

  94. Jordan BA, Trapaidze N, Gomes I, Nivarthi R, Devi LA. Oligomerization of opioid receptors with beta 2-adrenergic receptors: a role in trafficking and mitogen-activated protein kinase activation. Proc Natl Acad Sci USA 2001;98(1):343–8.

    Article  PubMed  CAS  Google Scholar 

  95. Rios C, Gomes I, Devi LA. Interactions between delta opioid receptors and alpha-adrenoceptors. Clin Exp Pharmacol Physiol 2004;31(11):833–6.

    Article  PubMed  CAS  Google Scholar 

  96. Gines S, Hillion J, Torvinen M, . Dopamine D1 and adenosine A1 receptors form functionally interacting heteromeric complexes. Proc Natl Acad Sci USA 2000;97(15):8606–11.

    Article  PubMed  CAS  Google Scholar 

  97. Rocheville M, Lange DC, Kumar U, Patel SC, Patel RC, Patel YC. Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. Science 2000;288(5463):154–7.

    Article  PubMed  CAS  Google Scholar 

  98. Kearn CS, Blake-Palmer K, Daniel E, Mackie K, Glass M. Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors enhances heterodimer formation: a mechanism for receptor cross-talk? Mol Pharmacol 2005;67(5):1697–704.

    Article  PubMed  CAS  Google Scholar 

  99. Waldhoer M, Fong J, Jones RM, . A heterodimer-selective agonist shows in vivo relevance of G protein-coupled receptor dimers. Proc Natl Acad Sci USA 2005;102(25):9050–5.

    Article  PubMed  CAS  Google Scholar 

  100. Chu P, Murray S, Lissin D, von Zastrow M. Delta and kappa opioid receptors are differentially regulated by dynamin-dependent endocytosis when activated by the same alkaloid agonist. J Biol Chem 1997;272(43):27124–30.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Neurology, Ernest Gallo Clinic and Research Center, University of California, San Francisco, CA, 94608

    Jennifer L. Whistler

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  1. Jennifer L. Whistler
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Correspondence to Jennifer L. Whistler .

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  1. VA Medical Center, 3710 SW US Veterans Hospital Road, 97239-2999, Portland, OR, USA

    Kim A. Neve

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Whistler, J.L. (2009). Ligand-Selective Receptor Desensitization and Endocytosis. In: Neve, K.A. (eds) Functional Selectivity of G Protein-Coupled Receptor Ligands. The Receptors. Humana Press. https://doi.org/10.1007/978-1-60327-335-0_4

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