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A network of phosphatidylinositol (4,5)-bisphosphate (PIP2) binding sites on the dopamine transporter regulates amphetamine behavior in Drosophila Melanogaster

Molecular Psychiatry volume 26, pages 4417–4430 (2021)Cite this article

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Abstract

Reward modulates the saliency of a specific drug exposure and is essential for the transition to addiction. Numerous human PET–fMRI studies establish a link between midbrain dopamine (DA) release, DA transporter (DAT) availability, and reward responses. However, how and whether DAT function and regulation directly participate in reward processes remains elusive. Here, we developed a novel experimental paradigm in Drosophila melanogaster to study the mechanisms underlying the psychomotor and rewarding properties of amphetamine (AMPH). AMPH principally mediates its pharmacological and behavioral effects by increasing DA availability through the reversal of DAT function (DA efflux). We have previously shown that the phospholipid, phosphatidylinositol (4, 5)-bisphosphate (PIP2), directly interacts with the DAT N-terminus to support DA efflux in response to AMPH. In this study, we demonstrate that the interaction of PIP2 with the DAT N-terminus is critical for AMPH-induced DAT phosphorylation, a process required for DA efflux. We showed that PIP2 also interacts with intracellular loop 4 at R443. Further, we identified that R443 electrostatically regulates DA efflux as part of a coordinated interaction with the phosphorylated N-terminus. In Drosophila, we determined that a neutralizing substitution at R443 inhibited the psychomotor actions of AMPH. We associated this inhibition with a decrease in AMPH-induced DA efflux in isolated fly brains. Notably, we showed that the electrostatic interactions of R443 specifically regulate the rewarding properties of AMPH without affecting AMPH aversion. We present the first evidence linking PIP2, DAT, DA efflux, and phosphorylation processes with AMPH reward.

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Fig. 1: PIP2/N-terminus interactions regulate DAT phosphorylation, a posttranslational modification that supports PIP2 independent DA efflux.
Fig. 2: R443A substitution reduced PIP2 binding and inhibited AMPH-induced DA efflux in vitro.
Fig. 3: Disrupting R443 electrostatic interactions inhibits DA efflux independent of DAT N-terminus phosphorylation.
Fig. 4: hDAT R443A limits central and behavioral responses to AMPH.
Fig. 5: In a two-choice consumption paradigm, hDAT R443A flies display diminished AMPH preference and continued AMPH aversion.

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References

  1. Winkelman TNA, Admon LK, Jennings L, Shippee ND, Richardson CR, Bart G. Evaluation of amphetamine-related hospitalizations and associated clinical outcomes and costs in the United States. JAMA Netw Open. 2018;1:e183758.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Berman S, O'Neill J, Fears S, Bartzokis G, London ED. Abuse of amphetamines and structural abnormalities in the brain. Ann N Y Acad Sci. 2008;1141:195–220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. UN Office DaC. World Drug Report 2017. Vienna, Austria: United Nations Publication; 2017. Report no.: 978-92-1-148291-1.

  4. Freyberg Z, Sonders MS, Aguilar JI, Hiranita T, Karam CS, Flores J, et al. Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain. Nat Commun. 2016;7:10652.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sulzer D, Sonders MS, Poulsen NW, Galli A. Mechanisms of neurotransmitter release by amphetamines: a review. Prog Neurobiol. 2005;75:406–33.

    Article  CAS  PubMed  Google Scholar 

  6. Hamilton PJ, Belovich AN, Khelashvili G, Saunders C, Erreger K, Javitch JA, et al. PIP2 regulates psychostimulant behaviors through its interaction with a membrane protein. Nat Chem Biol. 2014;10:582–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Pizzo AB, Karam CS, Zhang Y, Yano H, Freyberg RJ, Karam DS, et al. The membrane raft protein Flotillin-1 is essential in dopamine neurons for amphetamine-induced behavior in Drosophila. Mol Psychiatry. 2013;18:824–33.

    Article  CAS  PubMed  Google Scholar 

  8. Khoshbouei H, Sen N, Guptaroy B, Johnson L, Lund D, Gnegy ME, et al. N-terminal phosphorylation of the dopamine transporter is required for amphetamine-induced efflux. PLoS Biol. 2004;2:E78.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Cervinski MA, Foster JD, Vaughan RA. Psychoactive substrates stimulate dopamine transporter phosphorylation and down regulation by cocaine sensitive and protein kinase C dependent mechanisms. J Biol Chem. 2005;280:40442–9.

    Article  CAS  PubMed  Google Scholar 

  10. Fog JU, Khoshbouei H, Holy M, Owens WA, Vaegter CB, Sen N, et al. Calmodulin kinase II interacts with the dopamine transporter C terminus to regulate amphetamine-induced reverse transport. Neuron. 2006;51:417–29.

    Article  CAS  PubMed  Google Scholar 

  11. Johnson LA, Guptaroy B, Lund D, Shamban S, Gnegy ME. Regulation of amphetamine-stimulated dopamine efflux by protein kinase C beta. J Biol Chem. 2005;280:10914–9.

    Article  CAS  PubMed  Google Scholar 

  12. Binda F, Dipace C, Bowton E, Robertson SD, Lute BJ, Fog JU, et al. Syntaxin 1A interaction with the dopamine transporter promotes amphetamine-induced dopamine efflux. Mol Pharm. 2008;74:1101–8.

    Article  CAS  Google Scholar 

  13. Cervinski MA, Foster JD, Vaughan RA. Syntaxin 1A regulates dopamine transporter activity, phosphorylation and surface expression. Neuroscience. 2010;170:408–16.

    Article  CAS  PubMed  Google Scholar 

  14. Mauna JC, Harris SS, Pino JA, Edwards CM, DeChellis-Marks MR, Bassi CD, et al. G protein betagamma subunits play a critical role in the actions of amphetamine. Transl Psychiatry. 2019;9:81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Granas C, Ferrer J, Loland CJ, Javitch JA, Gether U. N-terminal truncation of the dopamine transporter abolishes phorbol ester- and substance P receptor-stimulated phosphorylation without impairing transporter internalization. J Biol Chem. 2003;278:4990–5000.

    Article  PubMed  CAS  Google Scholar 

  16. Foster JD, Pananusorn B, Vaughan RA. Dopamine transporters are phosphorylated on N-terminal serines in rat striatum. J Biol Chem. 2002;277:25178–86.

    Article  CAS  PubMed  Google Scholar 

  17. Cartier E, Hamilton PJ, Belovich AN, Shekar A, Campbell NG, Saunders C, et al. Rare autism-associated variants implicate syntaxin 1 (STX1 R26Q) phosphorylation and the dopamine transporter (hDAT R51W) in dopamine neurotransmission and behaviors. EBioMedicine. 2015;2:135–46.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Garcia-Olivares J, Baust T, Harris S, Hamilton P, Galli A, Amara SG, et al. Gbetagamma subunit activation promotes dopamine efflux through the dopamine transporter. Mol Psychiatry. 2017;22:1673–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Suh BC, Hille B. PIP2 is a necessary cofactor for ion channel function: how and why? Annu Rev Biophys. 2008;37:175–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. McLaughlin S, Murray D. Plasma membrane phosphoinositide organization by protein electrostatics. Nature. 2005;438:605–11.

    Article  CAS  PubMed  Google Scholar 

  21. Kadamur G, Ross EM. Mammalian phospholipase C. Annu Rev Physiol. 2013;75:127–54.

    Article  CAS  PubMed  Google Scholar 

  22. Czech MP. PIP2 and PIP3: complex roles at the cell surface. Cell. 2000;100:603–6.

    Article  CAS  PubMed  Google Scholar 

  23. Ben-Aissa K, Patino-Lopez G, Belkina NV, Maniti O, Rosales T, Hao JJ, et al. Activation of moesin, a protein that links actin cytoskeleton to the plasma membrane, occurs by phosphatidylinositol 4,5-bisphosphate (PIP2) binding sequentially to two sites and releasing an autoinhibitory linker. J Biol Chem. 2012;287:16311–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Whorton MR, MacKinnon R. Crystal structure of the mammalian GIRK2 K+ channel and gating regulation by G proteins, PIP2, and sodium. Cell. 2011;147:199–208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Thapa N, Anderson RA. PIP2 signaling, an integrator of cell polarity and vesicle trafficking in directionally migrating cells. Cell Adh Migr. 2012;6:409–12.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Buchmayer F, Schicker K, Steinkellner T, Geier P, Stubiger G, Hamilton PJ, et al. Amphetamine actions at the serotonin transporter rely on the availability of phosphatidylinositol-4,5-bisphosphate. PNAS. 2013;110:11642–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Khelashvili G, Stanley N, Sahai MA, Medina J, LeVine MV, Shi L, et al. Spontaneous inward opening of the dopamine transporter is triggered by PIP2-regulated dynamics of the N-terminus. ACS Chem Neurosci. 2015;6:1825–37.

    Article  CAS  PubMed  Google Scholar 

  28. Campbell NG, Shekar A, Aguilar JI, Peng D, Navratna V, Yang D, et al. Structural, functional, and behavioral insights of dopamine dysfunction revealed by a deletion in SLC6A3. PNAS. 2019;116:3853–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kume K, Kume S, Park SK, Hirsh J, Jackson FR. Dopamine is a regulator of arousal in the fruit fly. J Neurosci. 2005;25:7377–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Friggi-Grelin F, Coulom H, Meller M, Gomez D, Hirsh J, Birman S. Targeted gene expression in Drosophila dopaminergic cells using regulatory sequences from tyrosine hydroxylase. J Neurobiol. 2003;54:618–27.

    Article  CAS  PubMed  Google Scholar 

  31. Wang JW, Beck ES, McCabe BD. A modular toolset for recombination transgenesis and neurogenetic analysis of Drosophila. PLoS One. 2012;7:e42102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hamilton PJ, Campbell NG, Sharma S, Erreger K, Herborg Hansen F, Saunders C, et al. De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder. Mol Psychiatry. 2013;18:1315–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cheng MH, Block E, Hu F, Cobanoglu MC, Sorkin A, Bahar I. Insights into the modulation of dopamine transporter function by amphetamine, orphenadrine, and cocaine binding. Front Neurol. 2015;6:134.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Wu EL, Cheng X, Jo S, Rui H, Song KC, Dávila‐Contreras EM, et al. CHARMM‐GUI membrane builder toward realistic biological membrane simulations. J Comput Chem. 2014;35:1997–2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cheng MH, Ponzoni L, Sorkina T, Lee JY, Zhang S, Sorkin A, et al. Trimerization of dopamine transporter triggered by AIM-100 binding: Molecular mechanism and effect of mutations. Neuropharmacology. 2019;107676.

  36. Phillips JC, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E, et al. Scalable molecular dynamics with NAMD. J Comput Chem. 2005;26:1781–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Robbins J, Marsh SJ, Brown DA. Probing the regulation of M (Kv7) potassium channels in intact neurons with membrane-targeted peptides. J Neurosci. 2006;26:7950–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yu K, Jiang T, Cui Y, Tajkhorshid E, Hartzell HC. A network of phosphatidylinositol 4,5-bisphosphate binding sites regulate gating of the Ca2+ activated Cl- channel ANO1 (TMEM16A). 2019; 625897. https://doi.org/10.1073/pnas.1904012116.

  39. Yamamoto S, Seto ES. Dopamine dynamics and signaling in Drosophila: an overview of genes, drugs and behavioral paradigms. Exp Anim. 2014;63:107–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Claridge-Chang A, Roorda RD, Vrontou E, Sjulson L, Li H, Hirsh J, et al. Writing memories with light-addressable reinforcement circuitry. Cell. 2009;139:405–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kirkhart C, Scott K. Gustatory learning and processing in the Drosophila mushroom bodies. J Neurosci. 2015;35:5950–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Kaun KR, Azanchi R, Maung Z, Hirsh J, Heberlein U. A Drosophila model for alcohol reward. Nat Neurosci. 2011;14:612–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Brand AH, Perrimon N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development. 1993;118:401–15.

    Article  CAS  PubMed  Google Scholar 

  44. McClung C, Hirsh J. Stereotypic behavioral responses to free-base cocaine and the development of behavioral sensitization in Drosophila. Curr Biol. 1998;8:109–12.

    Article  CAS  PubMed  Google Scholar 

  45. Aguilar JI, Dunn M, Mingote S, Karam CS, Farino ZJ, Sonders MS, et al. Neuronal depolarization drives increased dopamine synaptic vesicle loading via VGLUT. Neuron. 2017;95:1074–88 e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Fleckenstein AE, Volz TJ, Riddle EL, Gibb JW, Hanson GR. New insights into the mechanism of action of amphetamines. Annu Rev Pharm Toxicol. 2007;47:681–98.

    Article  CAS  Google Scholar 

  47. Arias-Carrion O, Stamelou M, Murillo-Rodriguez E, Menendez-Gonzalez M, Poppel E. Dopaminergic reward system: a short integrative review. Int Arch Med. 2010;3:24.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Scaplen KM, Kaun KR. Reward from bugs to bipeds: a comparative approach to understanding how reward circuits function. J Neurogenet. 2016;30:133–48.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Dubol M, Trichard C, Leroy C, Sandu AL, Rahim M, Granger B, et al. Dopamine transporter and reward anticipation in a dimensional perspective: a multimodal brain imaging study. Neuropsychopharmacology. 2018;43:820–7.

    Article  CAS  PubMed  Google Scholar 

  50. Schott BH, Minuzzi L, Krebs RM, Elmenhorst D, Lang M, Winz OH, et al. Mesolimbic functional magnetic resonance imaging activations during reward anticipation correlate with reward-related ventral striatal dopamine release. J Neurosci. 2008;28:14311–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ja WW, Carvalho GB, Mak EM, de la Rosa NN, Fang AY, Liong JC, et al. Prandiology of Drosophila and the CAFE assay. PNAS. 2007;104:8253–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Diegelmann S, Jansen A, Jois S, Kastenholz K, Velo Escarcena L, Strudthoff N, et al. The CApillary FEeder assay measures food intake in Drosophila melanogaster. J Vis Exp. 2017;121:55024.

  53. Devineni AV, Heberlein U. Preferential ethanol consumption in Drosophila models features of addiction. Curr Biol. 2009;19:2126–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Foltin RW. The behavioral pharmacology of anorexigenic drugs in nonhuman primates: 30 years of progress. Behav Pharm. 2012;23:461–77.

    Article  CAS  Google Scholar 

  55. Cummings BS, Pati S, Sahin S, Scholpa NE, Monian P, Trinquero PM, et al. Differential effects of cocaine exposure on the abundance of phospholipid species in rat brain and blood. Drug Alcohol Depend. 2015;152:147–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ross BM, Turenne SD. Chronic cocaine administration reduces phospholipase A(2) activity in rat brain striatum. Prostaglandins Leukot Ess Fat Acids. 2002;66:479–83.

    Article  CAS  Google Scholar 

  57. Leussen DC, Psychostimulants Rong. Brain membrane lipids and dopamine transmission. J Biomolecular Res Therapeutics. 2016;5:1000143.

    Google Scholar 

  58. Marchant NJ, Kaganovsky K, Shaham Y, Bossert JM. Role of corticostriatal circuits in context-induced reinstatement of drug seeking. Brain Res. 2015;1628:219–32.

    Article  CAS  PubMed  Google Scholar 

  59. Ross BM, Moszczynska A, Peretti FJ, Adams V, Schmunk GA, Kalasinsky KS, et al. Decreased activity of brain phospholipid metabolic enzymes in human users of cocaine and methamphetamine. Drug Alcohol Depend. 2002;67:73–9.

    Article  CAS  PubMed  Google Scholar 

  60. Lee KH, Kim MY, Kim DH, Lee YS. Syntaxin 1A and receptor for activated C kinase interact with the N-terminal region of human dopamine transporter. Neurochem Res. 2004;29:1405–9.

    Article  CAS  PubMed  Google Scholar 

  61. Khelashvili G, Galli A, Weinstein H. Phosphatidylinositol 4,5-biphosphate (PIP(2)) lipids regulate the phosphorylation of syntaxin N-terminus by modulating both its position and local structure. Biochemistry. 2012;51:7685–98.

    Article  CAS  PubMed  Google Scholar 

  62. Amara SG, Kuhar MJ. Neurotransmitter transporters: recent progress. Annu Rev Neurosci. 1993;16:73–93.

    Article  CAS  PubMed  Google Scholar 

  63. Giros B, Caron MG. Molecular characterization of the dopamine transporter. Trends Pharm Sci. 1993;14:43–9.

    Article  CAS  PubMed  Google Scholar 

  64. Volkow ND, Fowler JS, Wang GJ. The addicted human brain viewed in the light of imaging studies: brain circuits and treatment strategies. Neuropharmacology. 2004;47 Suppl 1:3–13.

    Article  CAS  PubMed  Google Scholar 

  65. Cabib S, Orsini C, Le Moal M, Piazza PV. Abolition and reversal of strain differences in behavioral responses to drugs of abuse after a brief experience. Science. 2000;289:463–5.

    Article  CAS  PubMed  Google Scholar 

  66. O'Neill MF, Shaw G. Comparison of dopamine receptor antagonists on hyperlocomotion induced by cocaine, amphetamine, MK-801 and the dopamine D1 agonist C-APB in mice. Psychopharmacology. 1999;145:237–50.

    Article  CAS  PubMed  Google Scholar 

  67. Pignatelli M, Bonci A. Role of dopamine neurons in reward and aversion: a synaptic plasticity perspective. Neuron. 2015;86:1145–57.

    Article  CAS  PubMed  Google Scholar 

  68. Hu H. Reward and Aversion. Annu Rev Neurosci. 2016;39:297–324.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to acknowledge Saunders Consulting for the help in editing this manuscript. Research reported in this publication was supported by NIH R01-DA038058 (AG), NIH R01-DA035263 (AG and HJGM), NIH K99/R00-DA045795 (PJH), NIH F31-MH114316 (JIA), NIH P41-GM103712 (IB), and NIH P30-DA035778 (IB). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Author notes

  1. These authors contributed equally: Andrea N. Belovich, Jenny I. Aguilar

  2. These authors jointly supervised this work: Heinrich J. G. Matthies, Aurelio Galli

Authors and Affiliations

  1. Department of Pharmacology, Idaho College of Osteopathic Medicine, Meridian, ID, USA

    Andrea N. Belovich

  2. Department of Pharmacology, Vanderbilt University, Nashville, TN, USA

    Jenny I. Aguilar & Aparna Shekar

  3. Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA

    Jenny I. Aguilar, Samuel J. Mabry, Daniele Zanella, Aparna Shekar, Heinrich J. G. Matthies & Aurelio Galli

  4. Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Mary H. Cheng & Ivet Bahar

  5. Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA

    Peter J. Hamilton

  6. Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA

    Daniel J. Stanislowski & James D. Foster

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Contributions

JIA, AG, and HJGM conceptualized the study. JIA, ANB, SJM, MHC, DZ, PJH, DJS, AS, and HJGM carried out the experiments. JIA and AG conducted formal analyses of the data. JIA, AG, and HJGM provided conceptual advice and edited the manuscript. JIA and AG prepared data and figures and wrote the manuscript. AG and HJGM acquired funding and supervised the study. All authors contributed to the editing and review of the manuscript.

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Correspondence to Jenny I. Aguilar.

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Belovich, A.N., Aguilar, J.I., Mabry, S.J. et al. A network of phosphatidylinositol (4,5)-bisphosphate (PIP2) binding sites on the dopamine transporter regulates amphetamine behavior in Drosophila Melanogaster. Mol Psychiatry 26, 4417–4430 (2021). https://doi.org/10.1038/s41380-019-0620-0

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