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Arrestin recruitment to dopamine D2 receptor mediates locomotion but not incentive motivation

Molecular Psychiatry (2018) | Download Citation

Abstract

The dopamine (DA) D2 receptor (D2R) is an important target for the treatment of neuropsychiatric disorders such as schizophrenia and Parkinson’s disease. However, the development of improved therapeutic strategies has been hampered by our incomplete understanding of this receptor’s downstream signaling processes in vivo and how these relate to the desired and undesired effects of drugs. D2R is a G protein-coupled receptor (GPCR) that activates G protein-dependent as well as non-canonical arrestin-dependent signaling pathways. Whether these effector pathways act alone or in concert to facilitate specific D2R-dependent behaviors is unclear. Here, we report on the development of a D2R mutant that recruits arrestin but is devoid of G protein activity. When expressed virally in “indirect pathway” medium spiny neurons (iMSNs) in the ventral striatum of D2R knockout mice, this mutant restored basal locomotor activity and cocaine-induced locomotor activity in a manner indistinguishable from wild-type D2R, indicating that arrestin recruitment can drive locomotion in the absence of D2R-mediated G protein signaling. In contrast, incentive motivation was enhanced only by wild-type D2R, signifying a dissociation in the mechanisms that underlie distinct D2R-dependent behaviors, and opening the door to more targeted therapeutics.

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References

  1. 1.

    Beninger RJ. The role of dopamine in locomotor activity and learning. Brain Res. 1983;287:173–96.

  2. 2.

    Wise RA. Dopamine, learning and motivation. Nat Rev Neurosci. 2004;5:483–94.

  3. 3.

    Brozoski TJ, Brown RM, Rosvold HE, Goldman PS. Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey. Science. 1979;205:929–32.

  4. 4.

    Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: version III--the final common pathway. Schizophr Bull. 2009;35:549–62.

  5. 5.

    Dauer W, Przedborski S. Parkinson’s disease: mechanisms and models. Neuron. 2003;39:889–909.

  6. 6.

    Volkow ND, Fowler JS, Wang GJ, Swanson JM, Telang F. Dopamine in drug abuse and addiction: results of imaging studies and treatment implications. Arch Neurol. 2007;64:1575–9.

  7. 7.

    DiMaio S, Grizenko N, Joober R. Dopamine genes and attention-deficit hyperactivity disorder: a review. J Psychiatry Neurosci. 2003;28:27–38.

  8. 8.

    Denys D, Zohar J, Westenberg HG. The role of dopamine in obsessive-compulsive disorder: preclinical and clinical evidence. J Clin Psychiatry. 2004;65(Suppl 14):11–17.

  9. 9.

    Buse J, Schoenefeld K, Munchau A, Roessner V. Neuromodulation in Tourette syndrome: dopamine and beyond. Neurosci Biobehav Rev. 2013;37:1069–84.

  10. 10.

    Seeman P. Dopamine D2 receptors as treatment targets in schizophrenia. Clin Schizophr Relat Psychoses. 2010;4:56–73.

  11. 11.

    Goodman LS, Gilman A, Brunton LL. Goodman & Gilman’s manual of pharmacology and therapeutics. New York: McGraw-Hill Medical; 2008. ix, 1219 pp.

  12. 12.

    Brooks DJ. Dopamine agonists: their role in the treatment of Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2000;68:685–9.

  13. 13.

    Johnson PM, Kenny PJ. Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats. Nat Neurosci. 2010;13:635–41.

  14. 14.

    Tritsch NX, Sabatini BL. Dopaminergic modulation of synaptic transmission in cortex and striatum. Neuron. 2012;76:33–50.

  15. 15.

    Beaulieu JM, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev. 2011;63:182–217.

  16. 16.

    Centonze D, Grande C, Usiello A, Gubellini P, Erbs E, Martin AB, et al. Receptor subtypes involved in the presynaptic and postsynaptic actions of dopamine on striatal interneurons. J Neurosci. 2003;23:6245–54.

  17. 17.

    Ford CP. The role of D2-autoreceptors in regulating dopamine neuron activity and transmission. Neuroscience. 2014;282:13–22.

  18. 18.

    Wang H, Pickel VM. Dopamine D2 receptors are present in prefrontal cortical afferents and their targets in patches of the rat caudate-putamen nucleus. J Comp Neurol. 2002;442:392–404.

  19. 19.

    Surmeier DJ, Ding J, Day M, Wang Z, Shen W. D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons. Trends Neurosci. 2007;30:228–35.

  20. 20.

    Burke DA, Rotstein HG, Alvarez VA. Striatal local circuitry: a new framework for lateral inhibition. Neuron. 2017;96:267–84.

  21. 21.

    Greengard P, Allen PB, Nairn AC. Beyond the dopamine receptor: the DARPP- 32/protein phosphatase-1 cascade. Neuron. 1999;23:435–47.

  22. 22.

    Surmeier DJ, Eberwine J, Wilson CJ, Cao Y, Stefani A, Kitai ST. Dopamine receptor subtypes colocalize in rat striatonigral neurons. Proc Natl Acad Sci USA. 1992;89:10178–82.

  23. 23.

    Surmeier DJ, Bargas J, Hemmings HC Jr., Nairn AC, Greengard P. Modulation of calcium currents by a D1 dopaminergic protein kinase/phosphatase cascade in rat neostriatal neurons. Neuron. 1995;14:385–97.

  24. 24.

    Cepeda C, Chandler SH, Shumate LW, Levine MS. Persistent Na+ conductance in medium-sized neostriatal neurons: characterization using infrared videomicroscopy and whole cell patch-clamp recordings. J Neurophysiol. 1995;74:1343–8.

  25. 25.

    Hernandez-Lopez S, Bargas J, Surmeier DJ, Reyes A, Galarraga E. D1 receptor activation enhances evoked discharge in neostriatal medium spiny neurons by modulating an L-type Ca2+conductance. J Neurosci. 1997;17:3334–42.

  26. 26.

    Schiffmann SN, Lledo PM, Vincent JD. Dopamine D1 receptor modulates the voltage- gated sodium current in rat striatal neurones through a protein kinase A. J Physiol. 1995;483(Pt 1):95–107.

  27. 27.

    Andersson M, Konradi C, Cenci MA. cAMP response element-binding protein is required for dopamine-dependent gene expression in the intact but not the dopamine-denervated striatum. J Neurosci. 2001;21:9930–43.

  28. 28.

    Free RB, Chun LS, Moritz AE, Miller BN, Doyle TB, Conroy JL, et al. Discovery and characterization of a G protein-biased agonist that inhibits beta-arrestin recruitment to the D2 dopamine receptor. Mol Pharmacol. 2014;86:96–105.

  29. 29.

    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;276:37409–14.

  30. 30.

    DeWire SM, Ahn S, Lefkowitz RJ, Shenoy SK. Beta-arrestins and cell signaling. Annu Rev Physiol. 2007;69:483–510.

  31. 31.

    Allen JA, Yost JM, Setola V, Chen X, Sassano MF, Chen M, et al. Discovery of beta-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy. Proc Natl Acad Sci USA. 2011;108:18488–93.

  32. 32.

    Chen X, McCorvy JD, Fischer MG, Butler KV, Shen Y, Roth BL, et al. Discovery of G protein-biased D2 dopamine receptor partial agonists. J Med Chem. 2016;59:10601–18.

  33. 33.

    Chen X, Sassano MF, Zheng L, Setola V, Chen M, Bai X, et al. Structure-functional selectivity relationship studies of beta-arrestin-biased dopamine D(2) receptor agonists. J Med Chem. 2012;55:7141–53.

  34. 34.

    Conroy JL, Free RB, Sibley DR. Identification of G protein-biased agonists that fail to recruit beta-arrestin or promote internalization of the D1 dopamine receptor. ACS Chem Neurosci. 2015;6:681–92.

  35. 35.

    Beaulieu JM, Sotnikova TD, Marion S, Lefkowitz RJ, Gainetdinov RR, Caron MG. An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell. 2005;122:261–73.

  36. 36.

    Bateup HS, Santini E, Shen W, Birnbaum S, Valjent E, Surmeier DJ, et al. Distinct subclasses of medium spiny neurons differentially regulate striatal motor behaviors. Proc Natl Acad Sci USA. 2010;107:14845–50.

  37. 37.

    Gallo EF, Meszaros J, Sherman JD, Chohan MO, Teboul E, Choi CS, et al. Accumbens dopamine D2 receptors increase motivation by decreasing inhibitory transmission to the ventral pallidum. Nat Commun. 2018;9:1086.

  38. 38.

    Gallo EF, Salling MC, Feng B, Moron JA, Harrison NL, Javitch JA et al. Upregulation of dopamine D2 receptors in the nucleus accumbens indirect pathway increases locomotion but does not reduce alcohol consumption. Neuropsychopharmacology. 2015;40:1609-18.

  39. 39.

    Wang S, Che T, Levit A, Shoichet BK, Wacker D, Roth BL. Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone. Nature. 2018;555:269–73.

  40. 40.

    Guo W, Shi L, Javitch JA. The fourth transmembrane segment forms the interface of the dopamine D2 receptor homodimer. J Biol Chem. 2003;278:4385–8.

  41. 41.

    Clayton CC, Donthamsetti P, Lambert NA, Javitch JA, Neve KA. Mutation of three residues in the third intracellular loop of the dopamine D2 receptor creates an internalization-defective receptor. J Biol Chem. 2014;289:33663–75.

  42. 42.

    Donthamsetti P, Quejada JR, Javitch JA, Gurevich VV, Lambert NA. Using Bioluminescence Resonance Energy Transfer (BRET) to characterize agonist-induced arrestin recruitment to modified and unmodified G protein-coupled receptors. Curr Protoc Pharmacol. 2015; 70:2.14.1–14.

  43. 43.

    Hamdan FF, Rochdi MD, Breton B, Fessart D, Michaud DE, Charest PG, et al. Unraveling G protein-coupled receptor endocytosis pathways using real-time monitoring of agonist-promoted interaction between beta-arrestins and AP-2. J Biol Chem. 2007;282:29089–29100.

  44. 44.

    Jiang LI, Collins J, Davis R, Lin KM, DeCamp D, Roach T, et al. Use of a cAMP BRET sensor to characterize a novel regulation of cAMP by the sphingosine 1-phosphate/G13 pathway. J Biol Chem. 2007;282:10576–84.

  45. 45.

    Neve KA, Ford CP, Buck DC, Grandy DK, Neve RL, Phillips TJ. Normalizing dopamine D2 receptor-mediated responses in D2 null mutant mice by virus-mediated receptor restoration: comparing D2L and D2S. Neuroscience. 2013;248:479–87.

  46. 46.

    Bohn LM, Zhou L, Ho JH. Approaches to assess functional selectivity in GPCRs: evaluating G protein signaling in an endogenous environment. Methods Mol Biol. 2015;1335:177–89.

  47. 47.

    Hua T, Vemuri K, Pu M, Qu L, Han GW, Wu Y, et al. Crystal structure of the human cannabinoid receptor CB1. Cell. 2016;167:750–62. e714

  48. 48.

    Trifilieff P, Feng B, Urizar E, Winiger V, Ward RD, Taylor KM, et al. Increasing dopamine D2 receptor expression in the adult nucleus accumbens enhances motivation. Mol Psychiatry. 2013;18:1025–33.

  49. 49.

    Peterson SM, Pack TF, Wilkins AD, Urs NM, Urban DJ, Bass CE, et al. Elucidation of G-protein and beta-arrestin functional selectivity at the dopamine D2 receptor. Proc Natl Acad Sci USA. 2015;112:7097–102.

  50. 50.

    Lan H, Liu Y, Bell MI, Gurevich VV, Neve KA. A dopamine D2 receptor mutant capable of G protein-mediated signaling but deficient in arrestin binding. Mol Pharmacol. 2009;75:113–23.

  51. 51.

    Rose SJ, Pack TF, Peterson SM, Payne K, Borrelli E, Caron MG. Engineered D2R variants reveal the balanced and biased contributions of G-protein and beta-arrestin to dopamine-dependent functions. Neuropsychopharmacology. 2017;43:1164–73.

  52. 52.

    Nakajima K, Wess J. Design and functional characterization of a novel, arrestin-biased designer G protein-coupled receptor. Mol Pharmacol. 2012;82:575–82.

  53. 53.

    Ballesteros A, Weinstein H. Integrated methods for the construction of three-dimensional models of structure−function relations in G protein-coupled receptors. Methods Neurosci. 1995;25:366–428.

  54. 54.

    Rovati GE, Capra V, Neubig RR. The highly conserved DRY motif of class A G protein-coupled receptors: beyond the ground state. Mol Pharmacol. 2007;71:959–64.

  55. 55.

    Gales C, Rebois RV, Hogue M, Trieu P, Breit A, Hebert TE, et al. Real-time monitoring of receptor and G-protein interactions in living cells. Nat Methods. 2005;2:177–84.

  56. 56.

    Roth CB, Hanson MA, Stevens RC. Stabilization of the human beta2-adrenergic receptor TM4-TM3-TM5 helix interface by mutagenesis of Glu122(3.41), a critical residue in GPCR structure. J Mol Biol. 2008;376:1305–19.

  57. 57.

    Chien EY, Liu W, Zhao Q, Katritch V, Han GW, Hanson MA, et al. Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science. 2010;330:1091–5.

  58. 58.

    Gazi L, Nickolls SA, Strange PG. Functional coupling of the human dopamine D2 receptor with G alphai1, G alpha i2, G alpha i3 and G alpha o G proteins: evidence for agonist regulation of G protein selectivity. Br J Pharmacol. 2003;138:775–86.

  59. 59.

    Lane JR, Powney B, Wise A, Rees S, Milligan G. G protein coupling and ligand selectivity of the D2L and D3 dopamine receptors. J Pharmacol Exp Ther. 2008;325:319–30.

  60. 60.

    Jiang M, Spicher K, Boulay G, Wang Y, Birnbaumer L. Most central nervous system D2 dopamine receptors are coupled to their effectors by Go. Proc Natl Acad Sci USA. 2001;98:3577–82.

  61. 61.

    Marcott PF, Gong S, Donthamsetti P, Grinnell SG, Nelson MN, Newman AH, et al. Regional heterogeneity of D2-receptor signaling in the dorsal striatum and nucleus accumbens. Neuron. 2018;98:575–87. e574

  62. 62.

    Roberts DJ, Lin H, Strange PG. Investigation of the mechanism of agonist and inverse agonist action at D2 dopamine receptors. Biochem Pharmacol. 2004;67:1657–65.

  63. 63.

    Han Y, Moreira IS, Urizar E, Weinstein H, Javitch JA. Allosteric communication between protomers of dopamine class A GPCR dimers modulates activation. Nat Chem Biol. 2009;5:688–95.

  64. 64.

    Klewe IV, Nielsen SM, Tarpo L, Urizar E, Dipace C, Javitch JA, et al. Recruitment of beta-arrestin2 to the dopamine D2 receptor: insights into anti-psychotic and anti- parkinsonian drug receptor signaling. Neuropharmacology. 2008;54:1215–22.

  65. 65.

    Griffin G, Atkinson PJ, Showalter VM, Martin BR, Abood ME. Evaluation of cannabinoid receptor agonists and antagonists using the guanosine-5’-O-(3-[35S]thio)-triphosphate binding assay in rat cerebellar membranes. J Pharmacol Exp Ther. 1998;285:553–60.

  66. 66.

    Kelly MA, Rubinstein M, Phillips TJ, Lessov CN, Burkhart-Kasch S, Zhang G, et al. Locomotor activity in D2 dopamine receptor-deficient mice is determined by gene dosage, genetic background, and developmental adaptations. J Neurosci. 1998;18:3470–9.

  67. 67.

    Chausmer AL, Elmer GI, Rubinstein M, Low MJ, Grandy DK, Katz JL. Cocaine-induced locomotor activity and cocaine discrimination in dopamine D2 receptor mutant mice. Psychopharmacology (Berl). 2002;163:54–61.

  68. 68.

    Herlitze S, Garcia DE, Mackie K, Hille B, Scheuer T, Catterall WA. Modulation of Ca2+channels by G-protein beta gamma subunits. Nature. 1996;380:258–62.

  69. 69.

    Ikeda SR. Voltage-dependent modulation of N-type calcium channels by G-protein beta gamma subunits. Nature. 1996;380:255–8.

  70. 70.

    Martel P, Leo D, Fulton S, Berard M, Trudeau LE. Role of Kv1 potassium channels in regulating dopamine release and presynaptic D2 receptor function. PLoS ONE. 2011;6:e20402.

  71. 71.

    Kravitz AV, Freeze BS, Parker PR, Kay K, Thwin MT, Deisseroth K, et al. Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature. 2010;466:622–6.

  72. 72.

    Cazorla M, de Carvalho FD, Chohan MO, Shegda M, Chuhma N, Rayport S, et al. Dopamine D2 receptors regulate the anatomical and functional balance of basal ganglia circuitry. Neuron. 2014;81:153–64.

  73. 73.

    Carvalho Poyraz F, Holzner E, Bailey MR, Meszaros J, Kenney L, Kheirbek MA, et al. Decreasing Striatopallidal Pathway Function Enhances Motivation by Energizing the Initiation of Goal-Directed Action. J Neurosci: Off J Soc Neurosci. 2016;36:5988–6001.

  74. 74.

    Ferguson SM, Neumaier JF. Grateful DREADDs: engineered receptors reveal how neural circuits regulate behavior. Neuropsychopharmacol: Off Publ Am Coll Neuropsychopharmacol. 2012;37:296–7.

  75. 75.

    Bergson C, Levenson R, Goldman-Rakic PS, Lidow MS. Dopamine receptor-interacting proteins: the Ca(2+) connection in dopamine signaling. Trends Pharmacol Sci. 2003;24:486–92.

  76. 76.

    Beaulieu JM, Tirotta E, Sotnikova TD, Masri B, Salahpour A, Gainetdinov RR, et al. Regulation of Akt signaling by D2 and D3 dopamine receptors in vivo. J Neurosci. 2007;27:881–5.

  77. 77.

    Miller JS, Tallarida RJ, Unterwald EM. Cocaine-induced hyperactivity and sensitization are dependent on GSK3. Neuropharmacology. 2009;56:1116–23.

  78. 78.

    Beaulieu JM, Sotnikova TD, Yao WD, Kockeritz L, Woodgett JR, Gainetdinov RR, et al. Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Proc Natl Acad Sci USA. 2004;101:5099–104.

  79. 79.

    Li YC, Xi D, Roman J, Huang YQ, Gao WJ. Activation of glycogen synthase kinase-3 beta is required for hyperdopamine and D2 receptor-mediated inhibition of synaptic NMDA receptor function in the rat prefrontal cortex. J Neurosci. 2009;29:15551–63.

  80. 80.

    Li YC, Gao WJ. GSK-3beta activity and hyperdopamine-dependent behaviors. Neurosci Biobehav Rev. 2011;35:645–54.

  81. 81.

    Cooper AJ, Stanford IM. Dopamine D2 receptor mediated presynaptic inhibition of striatopallidal GABA(A) IPSCs in vitro. Neuropharmacology. 2001;41:62–71.

  82. 82.

    Tecuapetla F, Koos T, Tepper JM, Kabbani N, Yeckel MF. Differential dopaminergic modulation of neostriatal synaptic connections of striatopallidal axon collaterals. J Neurosci. 2009;29:8977–90.

  83. 83.

    Floran B, Floran L, Sierra A, Aceves J. D2 receptor-mediated inhibition of GABA release by endogenous dopamine in the rat globus pallidus. Neurosci Lett. 1997;237:1–4.

  84. 84.

    Kohnomi S, Koshikawa N, Kobayashi M. D(2)-like dopamine receptors differentially regulate unitary IPSCs depending on presynaptic GABAergic neuron subtypes in rat nucleus accumbens shell. J Neurophysiol. 2012;107:692–703.

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Acknowledgements

We thank Eric Teboul and Jeremy Sherman for technical assistance, and the Rodent Neurobehavioral Analysis Core at the New York Psychiatric Institute.

Author contributions

PD, EFG, DCB, ELS, YZ, and JRL performed the experiments. LMB, KAN, CK, and JAJ supervised the project. PD, EFG, CK, and JAJ wrote the manuscript, with input from JRL, LMB, and KAN. This work was supported by NIH grants DA044696 to PD, MH093672 to CK, DA009158 to LMB, MH54137 and DA022413 to JAJ, MH107648 to EFG, by Merit Review Award BX003279 to KAN from the US Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research, and Development, by the Lieber Center for Schizophrenia Research, and by the Hope for Depression Research Foundation.

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Author notes

    • Prashant Donthamsetti

    Present address: Department of Molecular and Cell Biology, University of California, Berkeley, CA, 94720, USA

  1. These authors contributed equally: Prashant Donthamsetti, Eduardo F. Gallo.

Affiliations

  1. Department of Pharmacology, Columbia University, New York, NY, 10032, USA

    • Prashant Donthamsetti
    • , Christoph Kellendonk
    •  & Jonathan A. Javitch
  2. Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, 10032, USA

    • Prashant Donthamsetti
    • , Eduardo F. Gallo
    • , Ying Zhu
    • , J. Robert Lane
    • , Christoph Kellendonk
    •  & Jonathan A. Javitch
  3. Department of Psychiatry, Columbia University, New York, NY, 10032, USA

    • Eduardo F. Gallo
    • , Ying Zhu
    • , J. Robert Lane
    • , Christoph Kellendonk
    •  & Jonathan A. Javitch
  4. Research Service, VA Portland Health Care System, United States Department of Veterans Affairs, Portland, OR, 97239, USA

    • David C. Buck
    •  & Kim A. Neve
  5. Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97239, USA

    • David C. Buck
    •  & Kim A. Neve
  6. Departments of Molecular Medicine and Neuroscience, Scripps Research, Jupiter, Florida, 33458, USA

    • Edward L. Stahl
    •  & Laura M. Bohn

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The authors declare that they have no conflict of interest.

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Correspondence to Jonathan A. Javitch.

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https://doi.org/10.1038/s41380-018-0212-4