Nonclassical pharmacology of the dopamine transporter: Atypical inhibitors, allosteric modulators, and partial substrates

Journal of Pharmacology and Experimental Therapeutics

Volumn 346, Issue 1, 2013, Pages 2-10

  Schmitt, Kyle C ^a   Rothman, Richard B ^b   Reith, Maarten E A ^a  

^a NEW YORK UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b NATIONAL INSTITUTE ON DRUG ABUSE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

(N BENZHYDRYL) 2 PHENYLQUINAZOLIN 4 AMINE; (N BUTYL) 3ALPHA [BIS(4 FLUOROPHENYL)METHOXY]TROPANE; (N DIPHENYLETHYL) 2 PHENYLQUINAZOLIN 4 AMINE; (N DIPHENYLPROPYL) 2 PHENYLQUINAZOLIN 4 AMINE; 3BETA (4 FLUOROPHENYL) 2BETA TROPANECARBOXYLIC ACID METHYL ESTER; 3BETA (4 METHYLPHENYL) 2BETA [3 (4 CHLOROPHENYL)ISOXAZOL 5 YL]TROPANE; AMFEBUTAMONE; AMPHETAMINE DERIVATIVE; BENZATROPINE; CARRIER PROTEIN; COCAINE; DOPAMINE; DOPAMINE RECEPTOR BLOCKING AGENT; DOPAMINE TRANSPORTER; ETHYLNAPHTHYLAMINOPROPANE; G PROTEIN COUPLED RECEPTOR; JHW 007; METHYLNAPHTHYLAMINOPROPANE; MODAFINIL; N ETHYL 3,4 METHYLENEDIOXYAMPHETAMINE; NAPHTHYLAMINOPROPANE; NEUROTRANSMITTER SODIUM SYMPORTER; NORADRENALINE TRANSPORTER; PAL 1045; PAL 1046; PAL 193; PAL 287; PAL 738; PSEUDOTROPINE BENZOATE; QUINAZOLINE DERIVATIVE; RIMCAZOLE; RTI 371; SEROTONIN TRANSPORTER; SORI 20040; SORI 20041; SORI 9084; TROPARIL; UNCLASSIFIED DRUG; UNINDEXED DRUG; VANOXERINE;

ALLOSTERISM; DOPAMINE RELEASE; DOPAMINE UPTAKE; DOPAMINERGIC SYSTEM; DRUG BINDING SITE; DRUG DESIGN; DRUG STRUCTURE; DRUG TARGETING; ENZYME SUBSTRATE COMPLEX; HUMAN; NEUROPHARMACOLOGY; NONHUMAN; PRIORITY JOURNAL; PROTEIN CONFORMATION; REVIEW; STRUCTURE ACTIVITY RELATION;

ALLOSTERIC REGULATION; ANIMALS; BIOLOGICAL TRANSPORT; BRAIN; DOPAMINE; DOPAMINE PLASMA MEMBRANE TRANSPORT PROTEINS; HUMANS; LIGANDS; MEMBRANE TRANSPORT MODULATORS; NERVE TISSUE PROTEINS; NEURONS; PROTEIN CONFORMATION; PROTEIN ISOFORMS;

EID: 84879305802     PISSN: 00223565     EISSN: 15210103     Source Type: Journal    
DOI: 10.1124/jpet.111.191056     Document Type: Review

References (67)

1. Bergman J, Madras BK, Johnson S.E., and Spealman RD (1989) Effects of cocaine and related drugs in nonhuman primates. III. Self-administration by squirrel monkeys. J Pharmacol Exp Ther 251:150-155.
2. Beuming T, Kniazeff J, Bergmann M.L., Shi L., Gracia L, Raniszewska K, Newman A.H., Javitch JA, Weinstein H, and Gether U, et al (2008) The binding sites for cocaine and dopamine in the dopamine transporter overlap. Nat Neurosci 11: 780-789.
3. Bisgaard H, Larsen MAB, Mazier S, Beuming T., Newman AH, Weinstein H, Shi L, Loland C.J., and Gether U (2011) The binding sites for benztropines and dopamine in the dopamine transporter overlap. Neuropharmacology 60:182-190.
4. Bulling S, Schicker K, Zhang Y.W., Steinkellner T., Stockner T, Gruber CW, Boehm S, Freissmuth M., Rudnick G, and Sitte HH, et al (2012) The mechanistic basis for noncompetitive ibogaine inhibition of serotonin and dopamine transporters. J Biol Chem 287:18524-18534.
5. Carroll FI, Blough BE, Abraham P, Mills A.C., Holleman JA, Wolckenhauer SA, Decker AM, Landavazo A, McElroy K.T., and Navarro HA, et al (2009) Synthesis and biological evaluation of bupropion analogues as potential pharmacotherapies for cocaine addiction. J Med Chem 52:6768-6781.
6. Chen N, Vaughan RA, and Reith ME (2001) The role of conserved tryptophan and acidic residues in the human dopamine transporter as characterized by site-directed mutagenesis. J Neurochem 77:1116-1127.
7. Chen N, Zhen J, and Reith MEA (2004) Mutation of Trp84 and Asp313 of the do-pamine transporter reveals similar mode of binding interaction for GBR12909 and benztropine as opposed to cocaine. J Neurochem 89:853-864.
8. Claxton DP, Quick M, Shi L., de Carvalho FD, Weinstein H, Javitch JA, and McHaourab HS (2010) Ion/substrate-dependent conformational dynamics of a bacterial homolog of neurotransmitter: sodium symporters. Nat Struct Mol Biol 17:822-829.
9. Cline EJ, Scheffel U, Boja J.W., Carroll FI, Katz JL, and Kuhar MJ (1992) Behavioral effects of novel cocaine analogs: a comparison with in vivo receptor binding potency. J Pharmacol Exp Ther 260:1174-1179.
10. Desai RI, Kopajtic TA, Koffarnus M, Newman A.H., and Katz JL (2005) Identification of a dopamine transporter ligand that blocks the stimulant effects of cocaine. J Neurosci 25:1889-1893.
11. Eriksen J, Jørgensen TN, and Gether U (2010) Regulation of dopamine transporter function by protein-protein interactions: new discoveries and methodological challenges. J Neurochem 113:27-41.
12. Felten A, Montag C, Markett S., Walter NT, and Reuter M (2011) Genetically determined dopamine availability predicts disposition for depression. Brain Behav 1:109-118.
13. Forrest LR, Krämer R, and Ziegler C (2011) The structural basis of secondary active transport mechanisms. Biochim Biophys Acta 1807:167-188.
14. Gainetdinov RR and Caron MG (2003) Monoamine transporters: from genes to behavior. Annu Rev Pharmacol Toxicol 43:261-284.
15. Gether U, Andersen PH, Larsson O.M., and Schousboe A (2006) Neurotransmitter transporters: molecular function of important drug targets. Trends Pharmacol Sci 27:375-383.
16. Greengard P (2001) The neurobiology of slow synaptic transmission. Science 294: 1024-1030.
17. Hadlock GC, Nelson CC, Baucum A.J., 2nd, Hanson GR, and Fleckenstein AE (2011) Ex vivo identification of protein-protein interactions involving the dopamine transporter. J Neurosci Methods 196:303-307.
18. Hiranita T, Soto PL, Kohut S.J., Kopajtic T., Cao J, Newman AH, Tanda G, and Katz JL (2011) Decreases in cocaine self-administration with dual inhibition of the do-pamine transporter and s receptors. J Pharmacol Exp Ther 339:662-677.
19. Jacobs MT, Zhang YW, Campbell S.D., and Rudnick G (2007) Ibogaine, a non-competitive inhibitor of serotonin transport, acts by stabilizing the cytoplasm-facing state of the transporter. J Biol Chem 282:29441-29447.
20. Jardetzky O (1966) Simple allosteric model for membrane pumps. Nature 211:969-970.
21. Katz JL, Izenwasser S, and Terry P (2000) Relationships among dopamine transporter affinities and cocaine-like discriminative-stimulus effects. Psychopharma-cology (Berl) 148:90-98.
22. +-dependent mechanism. J Biol Chem 278:12070-12077.
23. Kniazeff J, Shi L, Loland C.J., Javitch JA, Weinstein H, and Gether U (2008) An intracellular interaction network regulates conformational transitions in the do-pamine transporter. J Biol Chem 283:17691-17701.
24. Koldsø H, Christiansen AB, Sinning S, and Schiøtt B (2013) Comparative modeling of the human monoamine transporters: similarities in substrate binding. ACS Chem Neurosci 4:295-309.
25. Kopajtic TA, Liu Y, Surratt C.K., Donovan DM, Newman AH, and Katz JL (2010) Dopamine transporter-dependent and -independent striatal binding of the benztropine analog JHW 007, a cocaine antagonist with low abuse liability. J Pharmacol Exp Ther 335:703-714.
26. Kriel J, Haesendonckx S, Rubio-Texeira M, Van Zeebroeck G, and Thevelein JM (2011) From transporter to transceptor: signaling from transporters provokes reevaluation of complex trafficking and regulatory controls: endocytic internalization and intracellular trafficking of nutrient transceptors may, at least in part, be governed by their signaling function. Bioessays 33:870-879.
27. Krishnamurthy H and Gouaux E (2012) X-ray structures of Leu T in substrate-free outward-open and apo inward-open states. Nature 481:469-474.
28. Kurian MA, Li Y, Zhen J., Meyer E, Hai N, Christen H.J., Hoffmann GF, Jardine P, von Moers A, and Mordekar SR, et al (2011) Clinical and molecular characterisation of hereditary dopamine transporter deficiency syndrome: an observational cohort and experimental study. Lancet Neurol 10:54-62.
29. Li SM, Kopajtic TA, O'Callaghan MJ, Agoston GE, Cao J, Newman A.H., and Katz JL (2011) N-substituted benztropine analogs: selective dopamine transporter ligands with a fast onset of action and minimal cocaine-like behavioral effects. J Pharmacol Exp Ther 336:575-585.
30. Loland CJ, Desai RI, Zou M.F., Cao J., Grundt P, Gerstbrein K, Sitte H.H., Newman AH, Katz JL, and Gether U (2008) Relationship between conformational changes in the dopamine transporter and cocaine-like subjective effects of uptake inhibitors. Mol Pharmacol 73:813-823.
31. Loland CJ, Mereu M, Okunola O.M., Cao J., Prisinzano TE, Mazier S, Kopajtic T, Shi L., Katz JL, and Tanda G, et al (2012) R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse. Biol Psychiatry 72:405-413.
32. 2+) switch in the dopamine transporter: mutation of an intracellular tyrosine constitutively alters the conformational equilibrium of the transport cycle. Proc Natl Acad Sci USA 99:1683-1688.
33. Montague PR and Berns GS (2002) Neural economics and the biological substrates of valuation. Neuron 36:265-284.
34. Navarro HA, Howard JL, Pollard G.T., and Carroll FI (2009) Positive allosteric modulation of the human cannabinoid (CB) receptor by RTI-371, a selective inhibitor of the dopamine transporter. Br J Pharmacol 156:1178-1184.
35. Nyola A, Karpowich NK, Zhen J, Marden J., Reith ME, and Wang DN (2010) Substrate and drug binding sites in Leu T. Curr Opin Struct Biol 20:415-422.
36. Pariser JJ, Partilla JS, Dersch C.M., Ananthan S., and Rothman RB (2008) Studies of the biogenic amine transporters. 12. Identification of novel partial inhibitors of amphetamine-induced dopamine release. J Pharmacol Exp Ther 326:286-295.
37. Quick M, Shi L, Zehnpfennig B., Weinstein H, and Javitch JA (2012) Experimental conditions can obscure the second high-affinity site in Leu T. Nat Struct Mol Biol 19:207-211.
38. Quick M, Winther AML, Shi L, Nissen P., Weinstein H, and Javitch JA (2009) Binding of an octylglucoside detergent molecule in the second substrate (S2) site of Leu T establishes an inhibitor-bound conformation. Proc Natl Acad Sci USA 106: 5563-5568.
39. Reith ME, Berfield JL, Wang L.C., Ferrer JV, and Javitch JA (2001) The uptake inhibitors cocaine and benztropine differentially alter the conformation of the human dopamine transporter. J Biol Chem 276:29012-29018.
40. Ritz MC, Lamb RJ, Goldberg S.R., and Kuhar MJ (1987) Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science 237: 1219-1223.
41. Robertson SD, Matthies HJG, and Galli A (2009) A closer look at amphetamine-induced reverse transport and trafficking of the dopamine and norepinephrine transporters. Mol Neurobiol 39:73-80.
42. Rothman RB, Dersch CM, Ananthan S, and Partilla JS (2009) Studies of the biogenic amine transporters. 13. Identification of "agonist" and "antagonist" allosteric modulators of amphetamine-induced dopamine release. J Pharmacol Exp Ther 329:718-728.
43. Rothman RB, Partilla JS, Baumann M.H., Lightfoot-Siordia C, and Blough BE (2012) Studies of the biogenic amine transporters. 14. Identification of low-efficacy "partial" substrates for the biogenic amine transporters. J Pharmacol Exp Ther 341: 251-262.
44. Salamone JD, Correa M, Farrar A.M., Nunes EJ, and Pardo M (2009) Dopamine, behavioral economics, and effort. Front Behav Neurosci 3:13.
45. Schmitt KC, Mamidyala S, Biswas S., Dutta AK, and Reith MEA (2010) Bivalent phenethylamines as novel dopamine transporter inhibitors: evidence for multiple substrate-binding sites in a single transporter. J Neurochem 112:1605-1618.
46. Schmitt KC and Reith MEA (2010) Regulation of the dopamine transporter: aspects relevant to psychostimulant drugs of abuse. Ann N Y Acad Sci 1187:316-340.
47. Schmitt KC and Reith MEA (2011) The atypical stimulant and nootropic modafinil interacts with the dopamine transporter in a different manner than classical cocaine-like inhibitors. PLoS ONE 6:e25790.
48. Schmitt KC, Zhen J, Kharkar P., Mishra M, Chen N, Dutta A.K., and Reith MEA (2008) Interaction of cocaine-, benztropine-, and GBR12909-like compounds with wild-type and mutant human dopamine transporters: molecular features that differentially determine antagonist-binding properties. J Neurochem 107:928-940.
49. Shan J, Javitch JA, Shi L, and Weinstein H (2011) The substrate-driven transition to an inward-facing conformation in the functional mechanism of the dopamine transporter. PLoS ONE 6:e16350.
50. + and substrate is triggered by substrate in a second binding site. Mol Cell 30:667-677.
51. Singh SK, Piscitelli CL, Yamashita A, and Gouaux E (2008) A competitive inhibitor traps LeuT in an open-to-out conformation. Science 322:1655-1661.
52. Sitte HH, Huck S, Reither H., Boehm S, Singer EA, and Pifl C (1998) Carrier-mediated release, transport rates, and charge transfer induced by amphetamine, tyramine, and dopamine in mammalian cells transfected with the human dopamine transporter. J Neurochem 71:1289-1297.
53. Søgaard U, Michalow J., Butler B, Lund Laursen A, Ingersen SH, Skrumsager B.K., and Rafaelsen OJ (1990) A tolerance study of single and multiple dosing of the selective dopamine uptake inhibitor GBR 12909 in healthy subjects. Int Clin Psychopharmacol 5:237-251.
54. Tang L, Bai L, Wang W.H., and Jiang T (2010) Crystal structure of the carnitine transporter and insights into the antiport mechanism. Nat Struct Mol Biol 17: 492-496.
55. Taylor PM (2009) Amino acid transporters: éminences grises of nutrient signalling mechanisms? Biochem Soc Trans 37:237-241.
56. Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B, Weinstein H., Javitch JA, Roth BL, Christopoulos A, and Sexton PM, et al (2007) Functional selectivity and classical concepts of quantitative pharmacology. J Pharmacol Exp Ther 320: 1-13.
57. Volz TJ, Kim M, and Schenk JO (2004) Covalent and noncovalent chemical modifications of arginine residues decrease dopamine transporter activity. Synapse 52: 272-282.
58. Vosburg SK, Hart CL, Haney M, Rubin E., and Foltin RW (2010) Modafinil does not serve as a reinforcer in cocaine abusers. Drug Alcohol Depend 106:233-236.
59. Wang H and Gouaux E (2012) Substrate binds in the S1 site of the F253A mutant of LeuT, a neurotransmitter sodium symporter homologue. EMBO Rep 13:861-866.
60. Wee S, Carroll FI, and Woolverton WL (2006) A reduced rate of in vivo dopamine transporter binding is associated with lower relative reinforcing efficacy of stimulants. Neuropsychopharmacology 31:351-362.
61. Woolverton WL and Wang Z (2004) Relationship between injection duration, transporter occupancy and reinforcing strength of cocaine. Eur J Pharmacol 486:251-257.
62. - dependent neurotransmitter transporters. Nature 437:215-223.
63. Zhao C and Noskov SY (2011) The role of local hydration and hydrogen-bonding dynamics in ion and solute release from ion-coupled secondary transporters. Biochemistry 50:1848-1856.
64. Zhao Y, Terry D, Shi L., Weinstein H, Blanchard SC, and Javitch JA (2010) Single-molecule dynamics of gating in a neurotransmitter transporter homologue. Nature 465:188-193.
65. +-coupled neurotransmitter transporter homologue. Nature 474:109-113.
66. Zhou Z, Zhen J, Karpowich N.K., Goetz RM, Law CJ, Reith MEA, and Wang DN (2007) LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake. Science 317:1390-1393.
67. Zhou Z, Zhen J, Karpowich N.K., Law CJ, Reith MEA, and Wang DN (2009) Antidepressant specificity of serotonin transporter suggested by three LeuT-SSRI structures. Nat Struct Mol Biol 16:652-657.