Home LiteratureArticle Details
PMID: 25847498 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Review

Functional mechanisms of neurotransmitter transporters regulated by lipid-protein interactions of their terminal loops.

Biochimica et biophysica acta ·Vol. 1848 ·No. 9 ·2015-09-00 ·Pages 1765-74

Khelashvili G, Weinstein H

Abstract

The physiological functions of neurotransmitter:sodium symporters (NSS) in reuptake of neurotransmitters from the synapse into the presynaptic nerve have been shown to be complemented by their involvement, together with non-plasma membrane neurotransmitter transporters, in the reverse transport of substrate (efflux) in response to psychostimulants. Recent experimental evidence implicates highly anionic phosphatidylinositol 4,5-biphosphate (PIP(2)) lipids in such functions of the serotonin (SERT) and dopamine (DAT) transporters. Thus, for both SERT and DAT, neurotransmitter efflux has been shown to be strongly regulated by the presence of PIP(2) lipids in the plasma membrane, and the electrostatic interaction of the N-terminal region of DAT with the negatively charged PIP(2) lipids. We examine the experimentally established phenotypes in a structural context obtained from computational modeling based on recent crystallographic data. The results are shown to set the stage for a mechanistic understanding of physiological actions of neurotransmitter transporters in the NSS family of membrane proteins. This article is part of a Special Issue entitled: Lipid-protein interactions.

Keywords
Amphetamine-induced efflux Cell signaling and phosphorylation Continuum mean-field theory Electrostatic interactions Lipid segregation in the membrane Membrane composition and PIP(2) lipids Molecular dynamics Molecular dynamics simulations Psychostimulant drugs of abuse
MeSH Terms
Dopamine Plasma Membrane Transport Proteins/chemistry,metabolism Humans Membrane Lipids/chemistry,metabolism Membrane Transport Proteins/chemistry,metabolism Models, Molecular Neurotransmitter Transport Proteins/chemistry,metabolism Phosphatidylinositol 4,5-Diphosphate/chemistry,metabolism Protein Binding Protein Structure, Tertiary Serotonin Plasma Membrane Transport Proteins/chemistry,metabolism
Chemicals
Dopamine Plasma Membrane Transport Proteins Membrane Lipids Membrane Transport Proteins Neurotransmitter Transport Proteins Phosphatidylinositol 4,5-Diphosphate Serotonin Plasma Membrane Transport Proteins
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Khelashvili George
Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY, USA. Electronic address: gek2009@med.cornell.edu.
Weinstein Harel
Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY, USA; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, NY, USA.
References (104)
104 references, click to expand
  1. Single-molecule dynamics of gating in a neurotransmitter transporter homologue.
    Nature. 2010 May 13;465(7295):188-93 PMID: 20463731
  2. Ion/substrate-dependent conformational dynamics of a bacterial homolog of neurotransmitter:sodium symporters.
    Nat Struct Mol Biol. 2010 Jul;17(7):822-9 PMID: 20562855
  3. Modeling and dynamics of the inward-facing state of a Na+/Cl- dependent neurotransmitter transporter homologue.
    PLoS Comput Biol. 2010;6(8). pii: e1000905. doi: 10.1371/journal.pcbi.1000905 PMID: 20865057
  4. Neurotransmitter/sodium symporter orthologue LeuT has a single high-affinity substrate site.
    Nature. 2010 Dec 23;468(7327):1129-32 PMID: 21179170
  5. Regulation of monoamine transporters: Role of transporter phosphorylation.
    Pharmacol Ther. 2011 Feb;129(2):220-38 PMID: 20951731
  6. The substrate-driven transition to an inward-facing conformation in the functional mechanism of the dopamine transporter.
    PLoS One. 2011;6(1):e16350 PMID: 21298009
  7. Flotillin-1 is essential for PKC-triggered endocytosis and membrane microdomain localization of DAT.
    Nat Neurosci. 2011 Apr;14(4):469-77 PMID: 21399631
  8. Substrate-modulated gating dynamics in a Na+-coupled neurotransmitter transporter homologue.
    Nature. 2011 Jun 2;474(7349):109-13 PMID: 21516104
  9. SLC6 neurotransmitter transporters: structure, function, and regulation.
    Pharmacol Rev. 2011 Sep;63(3):585-640 PMID: 21752877
  10. Regulation of the catalytic activity of the EGF receptor.
    Curr Opin Struct Biol. 2011 Dec;21(6):777-84 PMID: 21868214
  11. Insights into transport mechanism from LeuT engineered to transport tryptophan.
    EMBO J. 2012 Jan 4;31(1):228-35 PMID: 21952050
  12. X-ray structures of LeuT in substrate-free outward-open and apo inward-open states.
    Nature. 2012 Jan 26;481(7382):469-74 PMID: 22230955
  13. Conformational dynamics of ligand-dependent alternating access in LeuT.
    Nat Struct Mol Biol. 2014 May;21(5):472-9 PMID: 24747939
  14. Not just an oil slick: how the energetics of protein-membrane interactions impacts the function and organization of transmembrane proteins.
    Biophys J. 2014 Jun 3;106(11):2305-16 PMID: 24896109
  15. PIP2 regulates psychostimulant behaviors through its interaction with a membrane protein.
    Nat Chem Biol. 2014 Jul;10(7):582-9 PMID: 24880859
  16. Missense dopamine transporter mutations associate with adult parkinsonism and ADHD.
    J Clin Invest. 2014 Jul;124(7):3107-20 PMID: 24911152
  17. Molecular mechanism of ligand recognition by membrane transport protein, Mhp1.
    EMBO J. 2014 Aug 18;33(16):1831-44 PMID: 24952894
  18. Structure and regulatory interactions of the cytoplasmic terminal domains of serotonin transporter.
    Biochemistry. 2014 Aug 26;53(33):5444-60 PMID: 25093911
  19. The second sodium site in the dopamine transporter controls cation permeation and is regulated by chloride.
    J Biol Chem. 2014 Sep 12;289(37):25764-73 PMID: 25063810
  20. Complete mapping of substrate translocation highlights the role of LeuT N-terminal segment in regulating transport cycle.
    PLoS Comput Biol. 2014 Oct;10(10):e1003879 PMID: 25299050
  21. Conformational cycle and ion-coupling mechanism of the Na+/hydantoin transporter Mhp1.
    Proc Natl Acad Sci U S A. 2014 Oct 14;111(41):14752-7 PMID: 25267652
  22. SLC6A3 coding variant Ala559Val found in two autism probands alters dopamine transporter function and trafficking.
    Transl Psychiatry. 2014;4:e464 PMID: 25313507
  23. The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants.
    Proc Natl Acad Sci U S A. 2014 Nov 4;111(44):E4779-88 PMID: 25331903
  24. A mechanism for intracellular release of Na+ by neurotransmitter/sodium symporters.
    Nat Struct Mol Biol. 2014 Nov;21(11):1006-12 PMID: 25282149
  25. Microseconds simulations reveal a new sodium-binding site and the mechanism of sodium-coupled substrate uptake by LeuT.
    J Biol Chem. 2015 Jan 2;290(1):544-55 PMID: 25381247
  26. Identification of a second substrate-binding site in solute-sodium symporters.
    J Biol Chem. 2015 Jan 2;290(1):127-41 PMID: 25398883
  27. Electrostatics of nanosystems: application to microtubules and the ribosome.
    Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10037-41 PMID: 11517324
  28. PIP(2) and proteins: interactions, organization, and information flow.
    Annu Rev Biophys Biomol Struct. 2002;31:151-75 PMID: 11988466
  29. A regulated interaction of syntaxin 1A with the antidepressant-sensitive norepinephrine transporter establishes catecholamine clearance capacity.
    J Neurosci. 2003 Mar 1;23(5):1697-709 PMID: 12629174
  30. Syntaxin 1A inhibits GABA flux, efflux, and exchange mediated by the rat brain GABA transporter GAT1.
    Mol Pharmacol. 2003 Oct;64(4):905-13 PMID: 14500747
  31. The effect of phosphorylation on amphetamine-mediated outward transport.
    Eur J Pharmacol. 2003 Oct 31;479(1-3):83-91 PMID: 14612140
  32. Regulating the conducting states of a mammalian serotonin transporter.
    Neuron. 2003 Oct 30;40(3):537-49 PMID: 14642278
  33. Amphetamine regulation of dopamine transport. Combined measurements of transporter currents and transporter imaging support the endocytosis of an active carrier.
    J Biol Chem. 2004 Mar 5;279(10):8966-75 PMID: 14699142
  34. N-terminal phosphorylation of the dopamine transporter is required for amphetamine-induced efflux.
    PLoS Biol. 2004 Mar;2(3):E78 PMID: 15024426
  35. Simple allosteric model for membrane pumps.
    Nature. 1966 Aug 27;211(5052):969-70 PMID: 5968307
  36. Phosphatidylinositol 4,5-bisphosphate binding to the pleckstrin homology domain of phospholipase C-delta1 enhances enzyme activity.
    J Biol Chem. 1996 Oct 11;271(41):25316-26 PMID: 8810295
  37. Amphetamine induces dopamine efflux through a dopamine transporter channel.
    Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3495-500 PMID: 15728379
  38. Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters.
    Nature. 2005 Sep 8;437(7056):215-23 PMID: 16041361
  39. Regulation of the dopamine transporter by phosphorylation.
    Handb Exp Pharmacol. 2006;(175):197-214 PMID: 16722237
  40. Neurotransmitter transporters: molecular function of important drug targets.
    Trends Pharmacol Sci. 2006 Jul;27(7):375-83 PMID: 16762425
  41. Transient formation of water-conducting states in membrane transporters.
    Proc Natl Acad Sci U S A. 2013 May 7;110(19):7696-701 PMID: 23610412
  42. Neurotransmitter transporters: structure meets function.
    Structure. 2013 May 7;21(5):694-705 PMID: 23664361
  43. A mechanistic role of Helix 8 in GPCRs: Computational modeling of the dopamine D2 receptor interaction with the GIPC1-PDZ-domain.
    Biochim Biophys Acta. 2015 Apr;1848(4):976-83 PMID: 25592838
  44. Computational modeling of the N-terminus of the human dopamine transporter and its interaction with PIP2 -containing membranes.
    Proteins. 2015 May;83(5):952-69 PMID: 25739722
  45. Calmodulin kinase II interacts with the dopamine transporter C terminus to regulate amphetamine-induced reverse transport.
    Neuron. 2006 Aug 17;51(4):417-29 PMID: 16908408
  46. A comprehensive structure-based alignment of prokaryotic and eukaryotic neurotransmitter/Na+ symporters (NSS) aids in the use of the LeuT structure to probe NSS structure and function.
    Mol Pharmacol. 2006 Nov;70(5):1630-42 PMID: 16880288
  47. Calcium-dependent interactions of the human norepinephrine transporter with syntaxin 1A.
    Mol Cell Neurosci. 2007 Feb;34(2):251-60 PMID: 17188889
  48. Antidepressant binding site in a bacterial homologue of neurotransmitter transporters.
    Nature. 2007 Aug 23;448(7156):952-6 PMID: 17687333
  49. Substrate binding and formation of an occluded state in the leucine transporter.
    Biophys J. 2008 Mar 1;94(5):1600-12 PMID: 18024499
  50. Protein diffusion on charged membranes: a dynamic mean-field model describes time evolution and lipid reorganization.
    Biophys J. 2008 Apr 1;94(7):2580-97 PMID: 18065451
  51. Sodium-coupled neurotransmitter transporters.
    Chem Rev. 2008 May;108(5):1654-68 PMID: 18393466
  52. Macromolecular modeling with rosetta.
    Annu Rev Biochem. 2008;77:363-82 PMID: 18410248
  53. An intracellular interaction network regulates conformational transitions in the dopamine transporter.
    J Biol Chem. 2008 Jun 20;283(25):17691-701 PMID: 18426798
  54. The mechanism of a neurotransmitter:sodium symporter--inward release of Na+ and substrate is triggered by substrate in a second binding site.
    Mol Cell. 2008 Jun 20;30(6):667-77 PMID: 18570870
  55. Structures of LeuT in bicelles define conformation and substrate binding in a membrane-like context.
    Nat Struct Mol Biol. 2012 Feb;19(2):212-9 PMID: 22245965
  56. Simple transporter trafficking model for amphetamine-induced dopamine efflux.
    Synapse. 2007 Jul;61(7):500-14 PMID: 17415796
  57. Experimental conditions can obscure the second high-affinity site in LeuT.
    Nat Struct Mol Biol. 2012 Feb;19(2):207-11 PMID: 22245968
  58. Constraints imposed by the membrane selectively guide the alternating access dynamics of the glutamate transporter GltPh.
    Biophys J. 2012 Mar 21;102(6):1331-40 PMID: 22455916
  59. Structure and mechanism of a glutamate-GABA antiporter.
    Nature. 2012 Mar 29;483(7391):632-6 PMID: 22407317
  60. Attention deficit/hyperactivity disorder-derived coding variation in the dopamine transporter disrupts microdomain targeting and trafficking regulation.
    J Neurosci. 2012 Apr 18;32(16):5385-97 PMID: 22514303
  61. The solute carrier 6 family of transporters.
    Br J Pharmacol. 2012 Sep;167(2):256-78 PMID: 22519513
  62. Dopamine transporter phosphorylation site threonine 53 regulates substrate reuptake and amphetamine-stimulated efflux.
    J Biol Chem. 2012 Aug 24;287(35):29702-12 PMID: 22722938
  63. Substrate binds in the S1 site of the F253A mutant of LeuT, a neurotransmitter sodium symporter homologue.
    EMBO Rep. 2012 Sep;13(9):861-6 PMID: 22836580
  64. Ion-controlled conformational dynamics in the outward-open transition from an occluded state of LeuT.
    Biophys J. 2012 Sep 5;103(5):878-88 PMID: 23009837
  65. Phosphatidylinositol 4,5-biphosphate (PIP(2)) lipids regulate the phosphorylation of syntaxin N-terminus by modulating both its position and local structure.
    Biochemistry. 2012 Oct 2;51(39):7685-98 PMID: 22950482
  66. Mutational analysis of the high-affinity zinc binding site validates a refined human dopamine transporter homology model.
    PLoS Comput Biol. 2013;9(2):e1002909 PMID: 23436987
  67. SLC6 transporters: structure, function, regulation, disease association and therapeutics.
    Mol Aspects Med. 2013 Apr-Jun;34(2-3):197-219 PMID: 23506866
  68. The cost of living in the membrane: a case study of hydrophobic mismatch for the multi-segment protein LeuT.
    Chem Phys Lipids. 2013 Apr;169:27-38 PMID: 23376428
  69. Chloride binding site of neurotransmitter sodium symporters.
    Proc Natl Acad Sci U S A. 2013 May 21;110(21):8489-94 PMID: 23641004
  70. Ligand induced conformational changes of the human serotonin transporter revealed by molecular dynamics simulations.
    PLoS One. 2013;8(6):e63635 PMID: 23776432
  71. The membrane raft protein Flotillin-1 is essential in dopamine neurons for amphetamine-induced behavior in Drosophila.
    Mol Psychiatry. 2013 Jul;18(7):824-33 PMID: 22710269
  72. Amphetamine actions at the serotonin transporter rely on the availability of phosphatidylinositol-4,5-bisphosphate.
    Proc Natl Acad Sci U S A. 2013 Jul 9;110(28):11642-7 PMID: 23798435
  73. Phosphoinositides: tiny lipids with giant impact on cell regulation.
    Physiol Rev. 2013 Jul;93(3):1019-137 PMID: 23899561
  74. Coupled global and local changes direct substrate translocation by neurotransmitter-sodium symporter ortholog LeuT.
    Biophys J. 2013 Aug 6;105(3):630-9 PMID: 23931311
  75. Mechanisms of dopamine transporter regulation in normal and disease states.
    Trends Pharmacol Sci. 2013 Sep;34(9):489-96 PMID: 23968642
  76. X-ray structure of dopamine transporter elucidates antidepressant mechanism.
    Nature. 2013 Nov 7;503(7474):85-90 PMID: 24037379
  77. De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder.
    Mol Psychiatry. 2013 Dec;18(12):1315-23 PMID: 23979605
  78. The SLC6 transporters: perspectives on structure, functions, regulation, and models for transporter dysfunction.
    Pflugers Arch. 2014 Jan;466(1):25-42 PMID: 24337881
  79. N-terminus regulation of VMAT2 mediates methamphetamine-stimulated efflux.
    Neuroscience. 2014 Feb 14;259:194-202 PMID: 24321511
  80. How LeuT shapes our understanding of the mechanisms of sodium-coupled neurotransmitter transporters.
    J Physiol. 2014 Mar 1;592(5):863-9 PMID: 23878376
  81. Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood.
    Brain. 2014 Apr;137(Pt 4):1107-19 PMID: 24613933
  82. NbIT--a new information theory-based analysis of allosteric mechanisms reveals residues that underlie function in the leucine transporter LeuT.
    PLoS Comput Biol. 2014 May;10(5):e1003603 PMID: 24785005
  83. PIP2 is a necessary cofactor for ion channel function: how and why?
    Annu Rev Biophys. 2008;37:175-95 PMID: 18573078
  84. The binding sites for cocaine and dopamine in the dopamine transporter overlap.
    Nat Neurosci. 2008 Jul;11(7):780-9 PMID: 18568020
  85. Anomalous dopamine release associated with a human dopamine transporter coding variant.
    J Neurosci. 2008 Jul 9;28(28):7040-6 PMID: 18614672
  86. Mechanism for alternating access in neurotransmitter transporters.
    Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10338-43 PMID: 18647834
  87. The crystal structure of a sodium galactose transporter reveals mechanistic insights into Na+/sugar symport.
    Science. 2008 Aug 8;321(5890):810-4 PMID: 18599740
  88. Calcium/calmodulin-dependent kinase II regulates the interaction between the serotonin transporter and syntaxin 1A.
    Neuropharmacology. 2008 Oct;55(5):763-70 PMID: 18602929
  89. Syntaxin 1A interaction with the dopamine transporter promotes amphetamine-induced dopamine efflux.
    Mol Pharmacol. 2008 Oct;74(4):1101-8 PMID: 18617632
  90. Structure and molecular mechanism of a nucleobase-cation-symport-1 family transporter.
    Science. 2008 Oct 31;322(5902):709-13 PMID: 18927357
  91. A competitive inhibitor traps LeuT in an open-to-out conformation.
    Science. 2008 Dec 12;322(5908):1655-61 PMID: 19074341
  92. A juxtamembrane mutation in the N terminus of the dopamine transporter induces preference for an inward-facing conformation.
    Mol Pharmacol. 2009 Mar;75(3):514-24 PMID: 19098122
  93. Molecular basis of transport and regulation in the Na(+)/betaine symporter BetP.
    Nature. 2009 Mar 5;458(7234):47-52 PMID: 19262666
  94. Binding of an octylglucoside detergent molecule in the second substrate (S2) site of LeuT establishes an inhibitor-bound conformation.
    Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5563-8 PMID: 19307590
  95. Structure and mechanism of an amino acid antiporter.
    Science. 2009 Jun 19;324(5934):1565-8 PMID: 19478139
  96. Monoamine transporter as a target molecule for psychostimulants.
    Int Rev Neurobiol. 2009;85:29-33 PMID: 19607959
  97. Structure of a prokaryotic virtual proton pump at 3.2 A resolution.
    Nature. 2009 Aug 20;460(7258):1040-3 PMID: 19578361
  98. Structure and mechanism of a Na+-independent amino acid transporter.
    Science. 2009 Aug 21;325(5943):1010-4 PMID: 19608859
  99. Modeling membrane deformations and lipid demixing upon protein-membrane interaction: the BAR dimer adsorption.
    Biophys J. 2009 Sep 16;97(6):1626-35 PMID: 19751667
  100. Ion-releasing state of a secondary membrane transporter.
    Biophys J. 2009 Dec 2;97(11):L29-31 PMID: 19948113
  101. The rocking bundle: a mechanism for ion-coupled solute flux by symmetrical transporters.
    Physiology (Bethesda). 2009 Dec;24:377-86 PMID: 19996368
  102. The N terminus of monoamine transporters is a lever required for the action of amphetamines.
    J Biol Chem. 2010 Apr 2;285(14):10924-38 PMID: 20118234
  103. Molecular basis of alternating access membrane transport by the sodium-hydantoin transporter Mhp1.
    Science. 2010 Apr 23;328(5977):470-3 PMID: 20413494
  104. Dysregulation of dopamine transporters via dopamine D2 autoreceptors triggers anomalous dopamine efflux associated with attention-deficit hyperactivity disorder.
    J Neurosci. 2010 Apr 28;30(17):6048-57 PMID: 20427663
Article Info
Journal
Biochimica et biophysica acta
Abbr.
Biochim Biophys Acta
ISSN
0006-3002
DOI
10.1016/j.bbamem.2015.03.025
Email
gek2009@med.cornell.edu
Published
2015-09-00
Epub
2015-00-04
Pages
1765-74
Language
English
Region
Netherlands
NLM ID
0217513
PMCID
PMC4501894
Subset
IM
Grants
NIDA NIH HHS · R01 DA035263 · United States
NIDA NIH HHS · 5R01DA035263 · United States
NIDA NIH HHS · R01 DA015170 · United States
NIDA NIH HHS · R01 DA017293 · United States
NIGMS NIH HHS · U54 GM087519 · United States
NIDA NIH HHS · P01 DA012408 · United States
External Links
PubMed source DOI: 10.1016/j.bbamem.2015.03.025 PMC Full Text
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2