Review Article | Published:

Regulation of monoamine transporters and receptors by lipid microdomains: implications for depression

Neuropsychopharmacologyvolume 43pages21652179 (2018) | Download Citation

Abstract

Lipid microdomains (“rafts”) are dynamic, nanoscale regions of the plasma membrane enriched in cholesterol and glycosphingolipids, that possess distinctive physicochemical properties including higher order than the surrounding membrane. Lipid microdomain integrity is thought to affect neurotransmitter signaling by regulating membrane-bound protein signaling. Among the proteins potentially affected are monoaminergic receptors and transporters. As dysfunction of monoaminergic neurotransmission is implicated in major depressive disorder and other neuropsychiatric conditions, interactions with lipid microdomains may be of clinical importance. This systematic review evaluates what is known about the molecular relationships of monoamine transporter and receptor regulation to lipid microdomains. The PubMed/MeSH database was searched for original studies published in English through August 2017 concerning relationships between lipid microdomains and serotonin, dopamine and norepinephrine transporters and receptors. Fifty-seven publications were identified and assessed. Strong evidence implicates lipid microdomains in the regulation of serotonin and norepinephrine transporters; serotonin 1A, 2A, 3A, and 7A receptors; and dopamine D1 and β2 adrenergic receptors. Results were conflicting or more complex regarding lipid microdomain associations with the dopamine transporter, D2, D3, and D5 receptors; and negative with respect to β1 adrenergic receptors. Indirect evidence suggests that antidepressants, lipid-lowering drugs, and polyunsaturated fatty acids may exert effects on depression and suicide by altering the lipid milieu, thereby affecting monoaminergic transporter and receptor signaling. The lipid composition of membrane subdomains is involved in localization and trafficking of specific monoaminergic receptors and transporters. Elucidating precise mechanisms whereby lipid microdomains modulate monoamine neurotransmission in clinical contexts can have critical implications for pharmacotherapeutic targeting.

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References

  1. 1.

    Lorent JH, Levental I. Structural determinants of protein partitioning into ordered membrane domains and lipid rafts. Chem Phys Lipids. 2015;192:23–32.

  2. 2.

    Levental I, Veatch SL. The continuing mystery of lipid rafts. J Mol Biol. 2016;428:4749–64.

  3. 3.

    Allen JA, Halverson-Tamboli RA, Rasenick MM. Lipid raft microdomains and neurotransmitter signalling. Nat Rev Neurosci. 2007;8:128–40.

  4. 4.

    Hancock JF. Lipid rafts: contentious only from simplistic standpoints. Nat Rev Mol Cell Biol. 2006;7:456–62.

  5. 5.

    Pralle A, Keller P, Florin EL, Simons K, Horber JK. Sphingolipid-cholesterol rafts diffuse as small entities in the plasma membrane of mammalian cells. J Cell Biol. 2000;148:997–1008.

  6. 6.

    Varma R, Mayor S. GPI-anchored proteins are organized in submicron domains at the cell surface. Nature. 1998;394:798–801.

  7. 7.

    Wilson BS, Pfeiffer JR, Oliver JM. Observing FcepsilonRI signaling from the inside of the mast cell membrane. J Cell Biol. 2000;149:1131–42.

  8. 8.

    Friedrichson T, Kurzchalia TV. Microdomains of GPI-anchored proteins in living cells revealed by crosslinking. Nature. 1998;394:802–5.

  9. 9.

    Harder T, Scheiffele P, Verkade P, Simons K. Lipid domain structure of the plasma membrane revealed by patching of membrane components. J Cell Biol. 1998;141:929–42.

  10. 10.

    Head BP, Patel HH, Insel PA. Interaction of membrane/lipid rafts with the cytoskeleton: impact on signaling and function: membrane/lipid rafts, mediators of cytoskeletal arrangement and cell signaling. Biochim Biophys Acta. 2014;1838:532–45.

  11. 11.

    Trushina E, Du Charme J, Parisi J, McMurray CT. Neurological abnormalities in caveolin-1 knock out mice. Behav Brain Res. 2006;172:24–32.

  12. 12.

    Kovtun O, Tillu VA, Ariotti N, Parton RG, Collins BM. Cavin family proteins and the assembly of caveolae. J Cell Sci. 2015;128:1269–78.

  13. 13.

    Kokubo H, Helms JB, Ohno-Iwashita Y, Shimada Y, Horikoshi Y, Yamaguchi H. Ultrastructural localization of flotillin-1 to cholesterol-rich membrane microdomains, rafts, in rat brain tissue. Brain Res. 2003;965:83–90.

  14. 14.

    Lang DM, Lommel S, Jung M, Ankerhold R, Petrausch B, Laessing U, et al. Identification of reggie-1 and reggie-2 as plasma membrane-associated proteins which cocluster with activated GPI-anchored cell adhesion molecules in non-caveolar micropatches in neurons. J Neurobiol. 1998;37:502–23.

  15. 15.

    Glebov OO, Bright NA, Nichols BJ. Flotillin-1 defines a clathrin-independent endocytic pathway in mammalian cells. Nat Cell Biol. 2006;8:46–54.

  16. 16.

    Chang JC, Tomlinson ID, Warnement MR, Ustione A, Carneiro AM, Piston DW, et al. Single molecule analysis of serotonin transporter regulation using antagonist-conjugated quantum dots reveals restricted, p38 MAPK-dependent mobilization underlying uptake activation. J Neurosci. 2012;32:8919–29.

  17. 17.

    Munro S. Lipid rafts: elusive or illusive? Cell. 2003;115:377–88.

  18. 18.

    Owen DM, Williamson DJ, Magenau A, Gaus K. Sub-resolution lipid domains exist in the plasma membrane and regulate protein diffusion and distribution. Nat Commun. 2012;3:1256.

  19. 19.

    Frisz JF, Klitzing HA, Lou K, Hutcheon ID, Weber PK, Zimmerberg J, et al. Sphingolipid domains in the plasma membranes of fibroblasts are not enriched with cholesterol. J Biol Chem. 2013;288:16855–61.

  20. 20.

    Frisz JF, Lou K, Klitzing HA, Hanafin WP, Lizunov V, Wilson RL, et al. Direct chemical evidence for sphingolipid domains in the plasma membranes of fibroblasts. Proc Natl Acad Sci USA. 2013;110:E613–22.

  21. 21.

    Kraft ML. Plasma membrane organization and function: moving past lipid rafts. Mol Biol Cell. 2013;24:2765–68.

  22. 22.

    Kusumi A, Fujiwara TK, Chadda R, Xie M, Tsunoyama TA, Kalay Z, et al. Dynamic organizing principles of the plasma membrane that regulate signal transduction: commemorating the fortieth anniversary of Singer and Nicolson's fluid-mosaic model. Annu Rev Cell Dev Biol. 2012;28:215–50.

  23. 23.

    Kwik J, Boyle S, Fooksman D, Margolis L, Sheetz MP, Edidin M. Membrane cholesterol, lateral mobility, and the phosphatidylinositol 4,5-bisphosphate-dependent organization of cell actin. Proc Natl Acad Sci USA. 2003;100:13964–9.

  24. 24.

    Sevcsik E, Brameshuber M, Folser M, Weghuber J, Honigmann A, Schutz GJ. GPI-anchored proteins do not reside in ordered domains in the live cell plasma membrane. Nat Commun. 2015;6:6969.

  25. 25.

    Brenner B, Harney JT, Ahmed BA, Jeffus BC, Unal R, Mehta JL, et al. Plasma serotonin levels and the platelet serotonin transporter. J Neurochem. 2007;102:206–15.

  26. 26.

    Brown DA, Rose JK. Sorting of GPI-anchored proteins to glycolipid-enriched membrane subdomains during transport to the apical cell surface. Cell. 1992;68:533–44.

  27. 27.

    Babiychuk EB, Draeger A. Biochemical characterization of detergent-resistant membranes: a systematic approach. Biochem J. 2006;397:407–16.

  28. 28.

    Lichtenberg D, Goni FM, Heerklotz H. Detergent-resistant membranes should not be identified with membrane rafts. Trends Biochem Sci. 2005;30:430–6.

  29. 29.

    Heerklotz H. Triton promotes domain formation in lipid raft mixtures. Biophys J. 2002;83:2693–701.

  30. 30.

    Song KS, Li S, Okamoto T, Quilliam LA, Sargiacomo M, Lisanti MP. Co-purification and direct interaction of Ras with caveolin, an integral membrane protein of caveolae microdomains. Detergent-free purification of caveolae microdomains. J Biol Chem. 1996;271:9690–7.

  31. 31.

    Schnitzer JE, Oh P, Pinney E, Allard J. Filipin-sensitive caveolae-mediated transport in endothelium: reduced transcytosis, scavenger endocytosis, and capillary permeability of select macromolecules. J Cell Biol. 1994;127:1217–32.

  32. 32.

    Zidovetzki R, Levitan I. Use of cyclodextrins to manipulate plasma membrane cholesterol content: evidence, misconceptions and control strategies. Biochim Biophys Acta. 2007;1768:1311–24.

  33. 33.

    Sjogren B, Hamblin MW, Svenningsson P. Cholesterol depletion reduces serotonin binding and signaling via human 5-HT(7(a)) receptors. Eur J Pharmacol. 2006;552:1–10.

  34. 34.

    Bhatnagar A, Sheffler DJ, Kroeze WK, Compton-Toth B, Roth BL. Caveolin-1 interacts with 5-HT2A serotonin receptors and profoundly modulates the signaling of selected Galphaq-coupled protein receptors. J Biol Chem. 2004;279:34614–23.

  35. 35.

    Mystek P, Dutka P, Tworzydlo M, Dziedzicka-Wasylewska M, Polit A. The role of cholesterol and sphingolipids in the dopamine D1 receptor and G protein distribution in the plasma membrane. Biochim Biophys Acta. 2016;1861:1775–86.

  36. 36.

    Sjogren B, Svenningsson P. Depletion of the lipid raft constituents, sphingomyelin and ganglioside, decreases serotonin binding at human 5-HT7(a) receptors in HeLa cells. Acta Physiol. 2007;190:47–53.

  37. 37.

    Gaus K, Inoue T. New biological frontiers illuminated by molecular sensors and actuators. Biophys J. 2016;111:E01–02.

  38. 38.

    Shaikh SR, Boyle S, Edidin M. A high fat diet containing saturated but not unsaturated fatty acids enhances T cell receptor clustering on the nanoscale. PLEFA. 2015;100:1–4.

  39. 39.

    Mueller V, Honigmann A, Ringemann C, Medda R, Schwarzmann G, Eggeling C. FCS in STED microscopy: studying the nanoscale of lipid membrane dynamics. Methods Enzymol. 2013;519:1–38.

  40. 40.

    Zacharias DA, Violin JD, Newton AC, Tsien RY. Partitioning of lipid-modified monomeric GFPs into membrane microdomains of live cells. Science. 2002;296:913–6.

  41. 41.

    Ilegems E, Pick H, Deluz C, Kellenberger S, Vogel H. Ligand binding transmits conformational changes across the membrane-spanning region to the intracellular side of the 5-HT3 serotonin receptor. Chembiochem. 2005;6:2180–5.

  42. 42.

    Abu-Arish A, Pandzic E, Goepp J, Matthes E, Hanrahan JW, Wiseman PW. Cholesterol modulates CFTR confinement in the plasma membrane of primary epithelial cells. Biophys J. 2015;109:85–94.

  43. 43.

    Polozov IV, Gawrisch K. NMR detection of lipid domains. In: McIntosh TJ, editor. Lipid rafts. Totowa: Himana Press; 2007. p. 107–26.

  44. 44.

    Cenido JF, Itin B, Stark RE, Huang YY, Oquendo MA, John Mann J, et al. Characterization of lipid rafts in human platelets using nuclear magnetic resonance: a pilot study. Biochem Biophys Rep. 2017;10:132–6.

  45. 45.

    Butler B, Saha K, Rana T, Becker JP, Sambo D, Davari P, et al. Dopamine transporter activity is modulated by alpha-synuclein. J Biol Chem. 2015;290:29542–54.

  46. 46.

    Arapulisamy O, Mannangatti P, Jayanthi LD. Regulated norepinephrine transporter interaction with the neurokinin-1 receptor establishes transporter subcellular localization. J Biol Chem. 2013;288:28599–610.

  47. 47.

    Triantafilou M, Morath S, Mackie A, Hartung T, Triantafilou K. Lateral diffusion of Toll-like receptors reveals that they are transiently confined within lipid rafts on the plasma membrane. J Cell Sci. 2004;117:4007–14.

  48. 48.

    Nichols B. Caveosomes and endocytosis of lipid rafts. J Cell Sci. 2003;116:4707–14.

  49. 49.

    Rajendran L, Simons K. Lipid rafts and membrane dynamics. J Cell Sci. 2005;118:1099–102.

  50. 50.

    Le Roy C, Wrana JL. Clathrin- and non-clathrin-mediated endocytic regulation of cell signalling. Nat Rev Mol Cell Biol. 2005;6:112–26.

  51. 51.

    Magnani F, Tate CG, Wynne S, Williams C, Haase J. Partitioning of the serotonin transporter into lipid microdomains modulates transport of serotonin. J Biol Chem. 2004;279:38770–8.

  52. 52.

    Scanlon SM, Williams DC, Schloss P. Membrane cholesterol modulates serotonin transporter activity. Biochemistry. 2001;40:10507–13.

  53. 53.

    Mann JJ. The serotonergic system in mood disorders and suicidal behaviour. Philos Trans R Soc Lond B Biol Sci. 2013;368:20120537.

  54. 54.

    Owens MJ, Nemeroff CB. Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem. 1994;40:288–95.

  55. 55.

    Sellers EM, Higgins GA, Tompkins DM, Romach MK. Serotonin and alcohol drinking. NIDA Res Monogr. 1992;119:141–5.

  56. 56.

    Coccaro EF. Central serotonin and impulsive aggression. Br J Psychiatry. 1989;155:52–62.

  57. 57.

    Compagnon P, Ernouf D, Narcisse G, Daoust M. Serotonin in animal models of alcoholism. Alcohol Alcohol Suppl. 1993;2:215–9.

  58. 58.

    Carlsson A. Perspectives on the discovery of central monoaminergic neurotransmission. Annu Rev Neurosci. 1987;10:19–40.

  59. 59.

    Koob GF, Sanna PP, Bloom FE. Neuroscience of addiction. Neuron. 1998;21:467–76.

  60. 60.

    Bannon M, Granneman J. The dopamine transport. Potential involvement in neuropsychiatric disorders. In: Bloom F, Kupfer D, editors. Psychopharmacoogy: the fourth generation of progress. New York, NY: Raven Press; 1995. p. 179–87.

  61. 61.

    Ressler KJ, Nemeroff CB. Role of norepinephrine in the pathophysiology and treatment of mood disorders. Biol Psychiatry. 1999;46:1219–33.

  62. 62.

    Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry. 1965;122:509–22.

  63. 63.

    Klimek V, Stockmeier C, Overholser J, Meltzer HY, Kalka S, Dilley G, et al. Reduced levels of norepinephrine transporters in the locus coeruleus in major depression. J Neurosci. 1997;17:8451–8.

  64. 64.

    Leonard BE. The role of noradrenaline in depression: a review. J Psychopharmacol. 1997;11:S39–47.

  65. 65.

    Blier P, de Montigny C, Chaput Y. A role for the serotonin system in the mechanism of action of antidepressant treatments: preclinical evidence. J Clin Psychiatry. 1990;51:14–20.

  66. 66.

    Gray NA, Milak MS, DeLorenzo C, Ogden RT, Huang YY, Mann JJ, et al. Antidepressant treatment reduces serotonin-1A autoreceptor binding in major depressive disorder. Biol Psychiatry. 2013;74:26–31.

  67. 67.

    Ramamoorthy S, Shippenberg TS, Jayanthi LD. Regulation of monoamine transporters: Role of transporter phosphorylation. Pharmacol Ther. 2011;129:220–38.

  68. 68.

    Barker EL, Blakely RD. Norephinephrine and serotonin transporters: molecular targets of antidepressant drugs. In: Bloom FE, Kupfer DJ, editors. Psychopharmacology: the fourth generation of progress. New York, NY: Raven Press; 1995. p. 321–33.

  69. 69.

    Richelson E. Interactions of antidepressants with neurotransmitter transporters and receptors and their clinical relevance. J Clin Psychiatry. 2003;64:5–12.

  70. 70.

    Jayanthi LD, Vargas G, DeFelice LJ. Characterization of cocaine and antidepressant-sensitive norepinephrine transporters in rat placental trophoblasts. Br J Pharmacol. 2002;135:1927–34.

  71. 71.

    Li Q, Ma L, Innis RB, Seneca N, Ichise M, Huang H, et al. Pharmacological and genetic characterization of two selective serotonin transporter ligands: 2-[2-(dimethylaminomethylphenylthio)]-5-fluoromethylphenylamine (AFM) and 3-amino-4-[2-(dimethylaminomethyl-phenylthio)]benzonitrile (DASB). J Pharmacol Exp Ther. 2004;308:481–6.

  72. 72.

    Bengel D, Murphy DL, Andrews AM, Wichems CH, Feltner D, Heils A, et al. Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4-methylenedioxymethamphetamine ("Ecstasy") in serotonin transporter-deficient mice. Mol Pharmacol. 1998;53:649–55.

  73. 73.

    Rioux A, Fabre V, Lesch KP, Moessner R, Murphy DL, Lanfumey L, et al. Adaptive changes of serotonin 5-HT2A receptors in mice lacking the serotonin transporter. Neurosci Lett. 1999;262:113–16.

  74. 74.

    Sora I, Hall FS, Andrews AM, Itokawa M, Li XF, Wei HB, et al. Molecular mechanisms of cocaine reward: combined dopamine and serotonin transporter knockouts eliminate cocaine place preference. Proc Natl Acad Sci USA. 2001;98:5300–05.

  75. 75.

    Adriani W, Boyer F, Gioiosa L, Macri S, Dreyer JL, Laviola G. Increased impulsive behavior and risk proneness following lentivirus-mediated dopamine transporter over-expression in rats' nucleus accumbens. Neuroscience. 2009;159:47–58.

  76. 76.

    Gainetdinov RR, Caron MG. Monoamine transporters: from genes to behavior. Annu Rev Pharmacol Toxicol. 2003;43:261–84.

  77. 77.

    Gainetdinov RR, Wetsel WC, Jones SR, Levin ED, Jaber M, Caron MG. Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity. Science. 1999;283:397–401.

  78. 78.

    Hall FS, Li XF, Sora I, Xu F, Caron M, Lesch KP, et al. Cocaine mechanisms: enhanced cocaine, fluoxetine and nisoxetine place preferences following monoamine transporter deletions. Neuroscience. 2002;115:153–61.

  79. 79.

    Min C, Zheng M, Zhang X, Guo S, Kwon KJ, Shin CY, et al. N-linked glycosylation on the N-terminus of the dopamine D2 and D3 receptors determines receptor association with specific microdomains in the plasma membrane. Biochim Biophys Acta. 2015;1853:41–51.

  80. 80.

    Voulalas PJ, Schetz J, Undieh AS. Differential subcellular distribution of rat brain dopamine receptors and subtype-specific redistribution induced by cocaine. Mol Cell Neurosci. 2011;46:645–54.

  81. 81.

    Yu P, Yang Z, Jones JE, Wang Z, Owens SA, Mueller SC, et al. D1 dopamine receptor signaling involves caveolin-2 in HEK-293 cells. Kidney Int. 2004;66:2167–80.

  82. 82.

    Torres GE, Carneiro A, Seamans K, Fiorentini C, Sweeney A, Yao WD, et al. Oligomerization and trafficking of the human dopamine transporter. Mutational analysis identifies critical domains important for the functional expression of the transporter. J Biol Chem. 2003;278:2731–9.

  83. 83.

    Kocabas AM, Rudnick G, Kilic F. Functional consequences of homo- but not hetero-oligomerization between transporters for the biogenic amine neurotransmitters. J Neurochem. 2003;85:1513–20.

  84. 84.

    Anderluh A, Hofmaier T, Klotzsch E, Kudlacek O, Stockner T, Sitte HH, et al. Direct PIP2 binding mediates stable oligomer formation of the serotonin transporter. Nat Commun. 2017;8:14089.

  85. 85.

    Liu Y, Casey L, Pike LJ. Compartmentalization of phosphatidylinositol 4,5-bisphosphate in low-density membrane domains in the absence of caveolin. Biochem Biophys Res Commun. 1998;245:684–90.

  86. 86.

    Pike LJ, Casey L. Localization and turnover of phosphatidylinositol 4,5-bisphosphate in caveolin-enriched membrane domains. J Biol Chem. 1996;271:26453–6.

  87. 87.

    Khelashvili G, Weinstein H. Functional mechanisms of neurotransmitter transporters regulated by lipid–protein interactions of their terminal loops. Biochim Biophys Acta. 2015;1848:1765–74.

  88. 88.

    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. Proc Natl Acad Sci USA. 2013;110:11642–7.

  89. 89.

    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.

  90. 90.

    Samuvel DJ, Jayanthi LD, Bhat NR, Ramamoorthy S. A role for p38 mitogen-activated protein kinase in the regulation of the serotonin transporter: evidence for distinct cellular mechanisms involved in transporter surface expression. J Neurosci. 2005;25:29–41.

  91. 91.

    Whitworth TL, Herndon LC, Quick MW. Psychostimulants differentially regulate serotonin transporter expression in thalamocortical neurons. J Neurosci. 2002;22:RC192.

  92. 92.

    Carneiro AM, Blakely RD. Serotonin-, protein kinase C-, and Hic-5-associated redistribution of the platelet serotonin transporter. J Biol Chem. 2006;281:24769–80.

  93. 93.

    Renner U, Glebov K, Lang T, Papusheva E, Balakrishnan S, Keller B, et al. Localization of the mouse 5-hydroxytryptamine(1A) receptor in lipid microdomains depends on its palmitoylation and is involved in receptor-mediated signaling. Mol Pharmacol. 2007;72:502–13.

  94. 94.

    Jorgensen TN, Christensen PM, Gether U. Serotonin-induced down-regulation of cell surface serotonin transporter. Neurochem Int. 2014;73:107–12.

  95. 95.

    Myers CL, Lazo JS, Pitt BR. Translocation of protein kinase C is associated with inhibition of 5-HT uptake by cultured endothelial cells. Am J Physiol. 1989;257:L253–8.

  96. 96.

    Qian Y, Galli A, Ramamoorthy S, Risso S, DeFelice LJ, Blakely RD. Protein kinase C activation regulates human serotonin transporters in HEK-293 cells via altered cell surface expression. J Neurosci. 1997;17:45–57.

  97. 97.

    Sorensen L, Stromgaard K, Kristensen AS. Characterization of intracellular regions in the human serotonin transporter for phosphorylation sites. ACS Chem Biol. 2014;9:935–44.

  98. 98.

    Ramamoorthy S, Blakely RD. Phosphorylation and sequestration of serotonin transporters differentially modulated by psychostimulants. Science. 1999;285:763–6.

  99. 99.

    Foster JD, Adkins SD, Lever JR, Vaughan RA. Phorbol ester induced trafficking-independent regulation and enhanced phosphorylation of the dopamine transporter associated with membrane rafts and cholesterol. J Neurochem. 2008;105:1683–99.

  100. 100.

    Jones KT, Zhen J, Reith ME. Importance of cholesterol in dopamine transporter function. J Neurochem. 2012;123:700–15.

  101. 101.

    Adkins EM, Samuvel DJ, Fog JU, Eriksen J, Jayanthi LD, Vaegter CB, et al. Membrane mobility and microdomain association of the dopamine transporter studied with fluorescence correlation spectroscopy and fluorescence recovery after photobleaching. Biochemistry. 2007;46:10484–97.

  102. 102.

    Sorkina T, Hoover BR, Zahniser NR, Sorkin A. Constitutive and protein kinase C-induced internalization of the dopamine transporter is mediated by a clathrin-dependent mechanism. Traffic. 2005;6:157–70.

  103. 103.

    Vainio S, Jansen M, Koivusalo M, Rog T, Karttunen M, Vattulainen I, et al. Significance of sterol structural specificity. Desmosterol cannot replace cholesterol in lipid rafts. J Biol Chem. 2006;281:348–55.

  104. 104.

    Daniels GM, Amara SG. Regulated trafficking of the human dopamine transporter. Clathrin-mediated internalization and lysosomal degradation in response to phorbol esters. J Biol Chem. 1999;274:35794–801.

  105. 105.

    Hong WC, Amara SG. Membrane cholesterol modulates the outward facing conformation of the dopamine transporter and alters cocaine binding. J Biol Chem. 2010;285:32616–26.

  106. 106.

    Navaroli DM, Stevens ZH, Uzelac Z, Gabriel L, King MJ, Lifshitz LM, et al. The plasma membrane-associated GTPase Rin interacts with the dopamine transporter and is required for protein kinase C-regulated dopamine transporter trafficking. J Neurosci. 2011;31:13758–70.

  107. 107.

    Cremona ML, Matthies HJ, Pau K, Bowton E, Speed N, Lute BJ, et al. Flotillin-1 is essential for PKC-triggered endocytosis and membrane microdomain localization of DAT. Nat Neurosci. 2011;14:469–77.

  108. 108.

    Gabriel LR, Wu S, Kearney P, Bellve KD, Standley C, Fogarty KE, et al. Dopamine transporter endocytic trafficking in striatal dopaminergic neurons: differential dependence on dynamin and the actin cytoskeleton. J Neurosci. 2013;33:17836–46.

  109. 109.

    Saunders C, Ferrer JV, Shi L, Chen J, Merrill G, Lamb ME, et al. Amphetamine-induced loss of human dopamine transporter activity: an internalization-dependent and cocaine-sensitive mechanism. Proc Natl Acad Sci USA. 2000;97:6850–5.

  110. 110.

    Sorkina T, Caltagarone J, Sorkin A. Flotillins regulate membrane mobility of the dopamine transporter but are not required for its protein kinase C dependent endocytosis. Traffic. 2013;14:709–24.

  111. 111.

    Chi L, Reith ME. Substrate-induced trafficking of the dopamine transporter in heterologously expressing cells and in rat striatal synaptosomal preparations. J Pharmacol Exp Ther. 2003;307:729–36.

  112. 112.

    Chen R, Daining CP, Sun H, Fraser R, Stokes SL, Leitges M, et al. Protein kinase Cbeta is a modulator of the dopamine D2 autoreceptor-activated trafficking of the dopamine transporter. J Neurochem. 2013;125:663–72.

  113. 113.

    Jayanthi LD, Samuvel DJ, Ramamoorthy S. Regulated internalization and phosphorylation of the native norepinephrine transporter in response to phorbol esters. Evidence for localization in lipid rafts and lipid raft-mediated internalization. J Biol Chem. 2004;279:19315–26.

  114. 114.

    Mandela P, Ordway GA. The norepinephrine transporter and its regulation. J Neurochem. 2006;97:310–33.

  115. 115.

    Zhu MY, Ordway GA. Down-regulation of norepinephrine transporters on PC12 cells by transporter inhibitors. J Neurochem. 1997;68:134–41.

  116. 116.

    Fantini J, Barrantes FJ. Sphingolipid/cholesterol regulation of neurotransmitter receptor conformation and function. Biochim Biophys Acta. 2009;1788:2345–61.

  117. 117.

    Kalipatnapu S, Chattopadhyay A. Membrane organization of the human serotonin(1A) receptor monitored by detergent insolubility using GFP fluorescence. Mol Membr Biol. 2005;22:539–47.

  118. 118.

    Pucadyil TJ, Chattopadhyay A. Cholesterol modulates ligand binding and G-protein coupling to serotonin(1A) receptors from bovine hippocampus. Biochim Biophys Acta. 2004;1663:188–200.

  119. 119.

    Sjogren B, Csoregh L, Svenningsson P. Cholesterol reduction attenuates 5-HT1A receptor-mediated signaling in human primary neuronal cultures. Naunyn Schmiede Arch Pharmacol. 2008;378:441–6.

  120. 120.

    Jafurulla M, Tiwari S, Chattopadhyay A. Identification of cholesterol recognition amino acid consensus (CRAC) motif in G-protein coupled receptors. Biochem Biophys Res Commun. 2011;404:569–73.

  121. 121.

    Gutierrez MG, Mansfield KS, Malmstadt N. The functional activity of the human serotonin 5-HT1A receptor is controlled by lipid bilayer composition. Biophys J. 2016;110:2486–95.

  122. 122.

    Dreja K, Voldstedlund M, Vinten J, Tranum-Jensen J, Hellstrand P, Sward K. Cholesterol depletion disrupts caveolae and differentially impairs agonist-induced arterial contraction. Arterioscler Thromb Vasc Biol. 2002;22:1267–72.

  123. 123.

    Mialet-Perez J, D'Angelo R, Villeneuve C, Ordener C, Negre-Salvayre A, Parini A, et al. Serotonin 5-HT2A receptor-mediated hypertrophy is negatively regulated by caveolin-3 in cardiomyoblasts and neonatal cardiomyocytes. J Mol Cell Cardiol. 2012;52:502–10.

  124. 124.

    Sommer B, Montano LM, Carbajal V, Flores-Soto E, Ortega A, Ramirez-Oseguera R, et al. Extraction of membrane cholesterol disrupts caveolae and impairs serotonergic (5-HT2A) and histaminergic (H1) responses in bovine airway smooth muscle: role of Rho-kinase. Can J Physiol Pharmacol. 2009;87:180–95.

  125. 125.

    Wu ZS, Cheng H, Jiang Y, Melcher K, Xu HE. Ion channels gated by acetylcholine and serotonin: structures, biology, and drug discovery. Acta Pharmacol Sin. 2015;36:895–907.

  126. 126.

    Nothdurfter C, Tanasic S, Di Benedetto B, Rammes G, Wagner EM, Kirmeier T, et al. Impact of lipid raft integrity on 5-HT3 receptor function and its modulation by antidepressants. Neuropsychopharmacology. 2010;35:1510–9.

  127. 127.

    Eisensamer B, Uhr M, Meyr S, Gimpl G, Deiml T, Rammes G, et al. Antidepressants and antipsychotic drugs colocalize with 5-HT3 receptors in raft-like domains. J Neurosci. 2005;25:10198–206.

  128. 128.

    Nothdurfter C, Tanasic S, Rammes G, Rupprecht R. Modulation of ligand-gated ion channels as a novel pharmacological principle. Pharmacopsychiatry. 2011;44:S27–34.

  129. 129.

    Sjogren B, Svenningsson P. Caveolin-1 affects serotonin binding and cell surface levels of human 5-HT7(a) receptors. FEBS Lett. 2007;581:5115–21.

  130. 130.

    Beaulieu JM, Espinoza S, Gainetdinov RR. Dopamine receptors—IUPHAR review 13. Br J Pharmacol. 2015;172:1–23.

  131. 131.

    Obadiah J, Avidor-Reiss T, Fishburn CS, Carmon S, Bayewitch M, Vogel Z, et al. Adenylyl cyclase interaction with the D2 dopamine receptor family; differential coupling to Gi, Gz, and Gs. Cell Mol Neurobiol. 1999;19:653–64.

  132. 132.

    Ilani T, Fishburn CS, Levavi-Sivan B, Carmon S, Raveh L, Fuchs S. Coupling of dopamine receptors to G proteins: studies with chimeric D2/D3 dopamine receptors. Cell Mol Neurobiol. 2002;22:47–56.

  133. 133.

    Jaber M, Robinson SW, Missale C, Caron MG. Dopamine receptors and brain function. Neuropharmacology. 1996;35:1503–19.

  134. 134.

    Vickery RG, von Zastrow M. Distinct dynamin-dependent and -independent mechanisms target structurally homologous dopamine receptors to different endocytic membranes. J Cell Biol. 1999;144:31–3.

  135. 135.

    Kong MM, Hasbi A, Mattocks M, Fan T, O'Dowd BF, George SR. Regulation of D1 dopamine receptor trafficking and signaling by caveolin-1. Mol Pharmacol. 2007;72:1157–70.

  136. 136.

    Yu P, Sun M, Villar VA, Zhang Y, Weinman EJ, Felder RA, et al. Differential dopamine receptor subtype regulation of adenylyl cyclases in lipid rafts in human embryonic kidney and renal proximal tubule cells. Cell Signal. 2014;26:2521–9.

  137. 137.

    Sunahara RK, Guan HC, O'Dowd BF, Seeman P, Laurier LG, Ng G, et al. Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D1. Nature. 1991;350:614–9.

  138. 138.

    Paspalas CD, Goldman-Rakic PS. Microdomains for dopamine volume neurotransmission in primate prefrontal cortex. J Neurosci. 2004;24:5292–300.

  139. 139.

    Yang S, Yang Y, Yu P, Yang J, Jiang X, Villar VA, et al. Dopamine D1 and D5 receptors differentially regulate oxidative stress through paraoxonase 2 in kidney cells. Free Radic Res. 2015;49:397–410.

  140. 140.

    Sharma M, Celver J, Octeau JC, Kovoor A. Plasma membrane compartmentalization of D2 dopamine receptors. J Biol Chem. 2013;288:12554–68.

  141. 141.

    Celver J, Sharma M, Kovoor A. D(2)-dopamine receptors target regulator of G protein signaling 9-2 to detergent-resistant membrane fractions. J Neurochem. 2012;120:56–69.

  142. 142.

    Genedani S, Guidolin D, Leo G, Filaferro M, Torvinen M, Woods AS, et al. Computer-assisted image analysis of caveolin-1 involvement in the internalization process of adenosine A2A-dopamine D2 receptor heterodimers. J Mol Neurosci. 2005;26:177–84.

  143. 143.

    Iwata K, Ito K, Fukuzaki A, Inaki K, Haga T. Dynamin and rab5 regulate GRK2-dependent internalization of dopamine D2 receptors. Eur J Biochem. 1999;263:596–602.

  144. 144.

    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.

  145. 145.

    Villar VA, Jones JE, Armando I, Palmes-Saloma C, Yu P, Pascua AM, et al. G protein-coupled receptor kinase 4 (GRK4) regulates the phosphorylation and function of the dopamine D3 receptor. J Biol Chem. 2009;284:21425–34.

  146. 146.

    Kim KM, Gainetdinov RR, Laporte SA, Caron MG, Barak LS. G protein-coupled receptor kinase regulates dopamine D3 receptor signaling by modulating the stability of a receptor-filamin-beta-arrestin complex. A case of autoreceptor regulation. J Biol Chem. 2005;280:12774–80.

  147. 147.

    Xiang Y, Rybin VO, Steinberg SF, Kobilka B. Caveolar localization dictates physiologic signaling of beta 2-adrenoceptors in neonatal cardiac myocytes. J Biol Chem. 2002;277:34280–6.

  148. 148.

    Oner SS, Kaya AI, Onaran HO, Ozcan G, Ugur O. beta2-Adrenoceptor, Gs and adenylate cyclase coupling in purified detergent-resistant, low density membrane fractions. Eur J Pharmacol. 2010;630:42–52.

  149. 149.

    Ostrom RS, Bundey RA, Insel PA. Nitric oxide inhibition of adenylyl cyclase type 6 activity is dependent upon lipid rafts and caveolin signaling complexes. J Biol Chem. 2004;279:19846–53.

  150. 150.

    Rybin VO, Xu X, Lisanti MP, Steinberg SF. Differential targeting of beta -adrenergic receptor subtypes and adenylyl cyclase to cardiomyocyte caveolae. A mechanism to functionally regulate the cAMP signaling pathway. J Biol Chem. 2000;275:41447–57.

  151. 151.

    Ostrom RS, Gregorian C, Drenan RM, Xiang Y, Regan JW, Insel PA. Receptor number and caveolar co-localization determine receptor coupling efficiency to adenylyl cyclase. J Biol Chem. 2001;276:42063–9.

  152. 152.

    Valentine CD, Haggie PM. Confinement of beta(1)- and beta(2)-adrenergic receptors in the plasma membrane of cardiomyocyte-like H9c2 cells is mediated by selective interactions with PDZ domain and A-kinase anchoring proteins but not caveolae. Mol Biol Cell. 2011;22:2970–82.

  153. 153.

    Hanson MA, Cherezov V, Griffith MT, Roth CB, Jaakola VP, Chien EY, et al. A specific cholesterol binding site is established by the 2.8 A structure of the human beta2-adrenergic receptor. Structure. 2008;16:897–905.

  154. 154.

    Pontier SM, Percherancier Y, Galandrin S, Breit A, Gales C, Bouvier M. Cholesterol-dependent separation of the beta2-adrenergic receptor from its partners determines signaling efficacy: insight into nanoscale organization of signal transduction. J Biol Chem. 2008;283:24659–72.

  155. 155.

    DiPilato LM, Zhang J. The role of membrane microdomains in shaping beta2-adrenergic receptor-mediated cAMP dynamics. Mol Biosyst. 2009;5:832–7.

  156. 156.

    Wright PT, Nikolaev VO, O'Hara T, Diakonov I, Bhargava A, Tokar S, et al. Caveolin-3 regulates compartmentation of cardiomyocyte beta2-adrenergic receptor-mediated cAMP signaling. J Mol Cell Cardiol. 2014;67:38–48.

  157. 157.

    Oh P, Schnitzer JE. Segregation of heterotrimeric G proteins in cell surface microdomains. G(q) binds caveolin to concentrate in caveolae, whereas G(i) and G(s) target lipid rafts by default. Mol Biol Cell. 2001;12:685–98.

  158. 158.

    Allen JA, Yu JZ, Donati RJ, Rasenick MM. Beta-adrenergic receptor stimulation promotes G alpha s internalization through lipid rafts: a study in living cells. Mol Pharmacol. 2005;67:1493–504.

  159. 159.

    Allen JA, Yu JZ, Dave RH, Bhatnagar A, Roth BL, Rasenick MM. Caveolin-1 and lipid microdomains regulate Gs trafficking and attenuate Gs/adenylyl cyclase signaling. Mol Pharmacol. 2009;76:1082–93.

  160. 160.

    Muller HK, Wiborg O, Haase J. Subcellular redistribution of the serotonin transporter by secretory carrier membrane protein 2. J Biol Chem. 2006;281:28901–9.

  161. 161.

    Chamberlain LH, Burgoyne RD, Gould GW. SNARE proteins are highly enriched in lipid rafts in PC12 cells: implications for the spatial control of exocytosis. Proc Natl Acad Sci USA. 2001;98:5619–24.

  162. 162.

    Bjork K, Svenningsson P. Modulation of monoamine receptors by adaptor proteins and lipid rafts: role in some effects of centrally acting drugs and therapeutic agents. Annu Rev Pharmacol Toxicol. 2011;51:211–42.

  163. 163.

    Hernandez-Rapp J, Martin-Lanneree S, Hirsch TZ, Pradines E, Alleaume-Butaux A, Schneider B, et al. A PrP(C)-caveolin-Lyn complex negatively controls neuronal GSK3beta and serotonin 1B receptor. Sci Rep. 2014;4:4881.

  164. 164.

    Fakhoury M. Revisiting the serotonin hypothesis: implications for major depressive disorders. Mol Neurobiol. 2016;53:2778–86.

  165. 165.

    Erb SJ, Schappi JM, Rasenick MM. Antidepressants accumulate in lipid rafts independent of monoamine transporters to modulate redistribution of the G protein, Galphas. J Biol Chem. 2016;291:19725–33.

  166. 166.

    Donati RJ, Dwivedi Y, Roberts RC, Conley RR, Pandey GN, Rasenick MM. Postmortem brain tissue of depressed suicides reveals increased Gs alpha localization in lipid raft domains where it is less likely to activate adenylyl cyclase. J Neurosci. 2008;28:3042–50.

  167. 167.

    Menkes DB, Rasenick MM, Wheeler MA, Bitensky MW. Guanosine triphosphate activation of brain adenylate cyclase: enhancement by long-term antidepressant treatment. Science. 1983;219:65–7.

  168. 168.

    Toki S, Donati RJ, Rasenick MM. Treatment of C6 glioma cells and rats with antidepressant drugs increases the detergent extraction of G(s alpha) from plasma membrane. J Neurochem. 1999;73:1114–20.

  169. 169.

    Zhang L, Rasenick MM. Chronic treatment with escitalopram but not R-citalopram translocates Galpha(s) from lipid raft domains and potentiates adenylyl cyclase: a 5-hydroxytryptamine transporter-independent action of this antidepressant compound. J Pharmacol Exp Ther. 2010;332:977–84.

  170. 170.

    Donati RJ, Rasenick MM. Chronic antidepressant treatment prevents accumulation of gsalpha in cholesterol-rich, cytoskeletal-associated, plasma membrane domains (lipid rafts). Neuropsychopharmacology. 2005;30:1238–45.

  171. 171.

    Donati RJ, Rasenick MM. G protein signaling and the molecular basis of antidepressant action. Life Sci. 2003;73:1–17.

  172. 172.

    Fleischhacker WW, Hinterhuber H, Bauer H, Pflug B, Berner P, Simhandl C, et al. A multicenter double-blind study of three different doses of the new cAMP-phosphodiesterase inhibitor rolipram in patients with major depressive disorder. Neuropsychobiology. 1992;26:59–64.

  173. 173.

    Donati RJ, Schappi J, Czysz AH, Jackson A, Rasenick MM. Differential effects of antidepressants escitalopram versus lithium on Gs alpha membrane relocalization. BMC Neurosci. 2015;16:40.

  174. 174.

    Guesdon W, Kosaraju R, Brophy P, Clark A, Dillingham S, Aziz S, et al. Effects of fish oils on ex vivo B-cell responses of obese subjects upon BCR/TLR stimulation: a pilot study. J Nutr Biochem. 2018;53:72–80.

  175. 175.

    Simopoulos AP. Evolutionary aspects of diet: the omega-6/omega-3 ratio and the brain. Mol Neurobiol. 2011;44:203–15.

  176. 176.

    Lin PY, Huang SY, Su KP. A meta-analytic review of polyunsaturated fatty acid compositions in patients with depression. Biol Psychiatry. 2010;68:140–7.

  177. 177.

    Sublette ME, Hibbeln JR, Galfalvy H, Oquendo MA, Mann JJ. Omega-3 polyunsaturated essential fatty acid status as a predictor of future suicide risk. Am J Psychiatry. 2006;163:1100–2.

  178. 178.

    Huan M, Hamazaki K, Sun Y, Itomura M, Liu H, Kang W, et al. Suicide attempt and n-3 fatty acid levels in red blood cells: a case control study in China. Biol Psychiatry. 2004;56:490–6.

  179. 179.

    Lewis MD, Hibbeln JR, Johnson JE, Lin YH, Hyun DY, Loewke JD. Suicide deaths of active-duty US military and omega-3 fatty-acid status: a case-control comparison. J Clin Psychiatry 2011;72:1585–90.

  180. 180.

    Shaikh SR, Kinnun JJ, Leng X, Williams JA, Wassall SR. How polyunsaturated fatty acids modify molecular organization in membranes: insight from NMR studies of model systems. Biochim Biophys Acta. 2014;1848:211–9.

  181. 181.

    Shaikh SR, Wassall SR, Brown DA, Kosaraju R. N-3 polyunsaturated fatty acids, lipid microclusters, and vitamin E. Curr Top Membr. 2015;75:209–31.

  182. 182.

    Williams JA, Batten SE, Harris M, Rockett BD, Shaikh SR, Stillwell W, et al. Docosahexaenoic and eicosapentaenoic acids segregate differently between raft and nonraft domains. Biophys J. 2012;103:228–37.

  183. 183.

    Harris M, Kinnun JJ, Kosaraju R, Leng X, Wassall SR, Shaikh SR. Membrane disordering by eicosapentaenoic acid in B lymphomas is reduced by elongation to docosapentaenoic acid as revealed with solid-state nuclear magnetic resonance spectroscopy of model membranes. J Nutr. 2016;146:1283–9.

  184. 184.

    Martins JG. EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: evidence from a meta-analysis of randomized controlled trials. J Am Coll Nutr. 2009;28:525–42.

  185. 185.

    Martins JG, Bentsen H, Puri BK. Eicosapentaenoic acid appears to be the key omega-3 fatty acid component associated with efficacy in major depressive disorder: a critique of Bloch and Hannestad and updated meta-analysis. Mol Psychiatry. 2012;17:1144–9.

  186. 186.

    Sublette ME, Ellis SP, Geant AL, Mann JJ. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry. 2011;72:1577–84.

  187. 187.

    Czysz AH, Rasenick MM. G-protein signaling, lipid rafts and the possible sites of action for the antidepressant effects of n-3 polyunsaturated fatty acids. CNS Neurol Disord Drug Targets. 2013;12:466–73.

  188. 188.

    Guixa-Gonzalez R, Javanainen M, Gomez-Soler M, Cordobilla B, Domingo JC, Sanz F, et al. Membrane omega-3 fatty acids modulate the oligomerisation kinetics of adenosine A2A and dopamine D2 receptors. Sci Rep. 2016;6:19839.

  189. 189.

    Carotenuto F, Minieri M, Monego G, Fiaccavento R, Bertoni A, Sinigaglia F, et al. A diet supplemented with ALA-rich flaxseed prevents cardiomyocyte apoptosis by regulating caveolin-3 expression. Cardiovasc Res. 2013;100:422–31.

  190. 190.

    Folino A, Sprio AE, Di Scipio F, Berta GN, Rastaldo R. Alpha-linolenic acid protects against cardiac injury and remodelling induced by beta-adrenergic overstimulation. Food Funct. 2015;6:2231–9.

  191. 191.

    Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27:24–31.

  192. 192.

    Raison CL, Miller AH. Do cytokines really sing the blues? Cerebrum. 2013;2013:10.

  193. 193.

    Wong SW, Kwon MJ, Choi AM, Kim HP, Nakahira K, Hwang DH. Fatty acids modulate Toll-like receptor 4 activation through regulation of receptor dimerization and recruitment into lipid rafts in a reactive oxygen species-dependent manner. J Biol Chem. 2009;284:27384–92.

  194. 194.

    Muldoon MF, Manuck SB, Matthews KA. Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials. BMJ. 1990;301:309–14.

  195. 195.

    Muldoon MF, Manuck SB, Mendelsohn AB, Kaplan JR, Belle SH. Cholesterol reduction and non-illness mortality: meta-analysis of randomised clinical trials. BMJ. 2001;322:11–15.

  196. 196.

    Wu S, Ding Y, Wu F, Xie G, Hou J, Mao P. Serum lipid levels and suicidality: a meta-analysis of 65 epidemiological studies. J Psychiatry Neurosci. 2016;41:56–69.

  197. 197.

    Kaplan JR, Shively CA, Fontenot MB, Morgan TM, Howell SM, Manuck SB, et al. Demonstration of an association among dietary cholesterol, central serotonergic activity, and social behavior in monkeys. Psychosom Med. 1994;56:479–84.

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Funding

This study was supported in part by the following grants: K08 MH079033 (PI, MES), NIH R01AT008375 (PI, SRS), NIH 8G12 MD007603 (Area Leader, RES). Dr. JJM receives royalties for commercial use of the Columbia-Suicide Severity Rating Scale (C-SSRS) from the Research Foundation for Mental Hygiene.

Author information

Author notes

    • Joanne J. Liu

    Present address: Chestnut Hill Hospital, Philadelphia, PA, USA

    • Adrienne Hezghia

    Present address: Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA

    • Joshua F. Cenido

    Present address: Department of Psychiatry, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA

Affiliations

  1. Department of Molecular Imaging & Neuropathology, New York State Psychiatric Institute, New York, NY, USA

    • Joanne J. Liu
    • , Adrienne Hezghia
    • , Joshua F. Cenido
    • , J. John Mann
    •  & M. Elizabeth Sublette
  2. Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    • Saame Raza Shaikh
  3. Department of Chemistry and Biochemistry and CUNY Institute for Macromolecular Assemblies, The City College of New York, New York, NY, USA

    • Ruth E. Stark
  4. Ph.D. Program in Biochemistry, The Graduate Center of the City University of New York, New York, NY, USA

    • Ruth E. Stark
  5. Department of Psychiatry, Columbia University, New York, NY, USA

    • J. John Mann
    •  & M. Elizabeth Sublette
  6. Department of Radiology, Columbia University, New York, NY, USA

    • J. John Mann

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The authors declare no competing interests.

Corresponding author

Correspondence to M. Elizabeth Sublette.

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https://doi.org/10.1038/s41386-018-0133-6