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- SLC6 neurotransmitter transporter family
Contents
Overview
Members of the solute carrier family 6 (SLC6) of sodium- and (sometimes chloride-) dependent neurotransmitter transporters [1-3,5] are primarily plasma membrane located and may be divided into four subfamilies that transport monoamines, GABA, glycine and neutral amino acids, plus the related bacterial NSS transporters [6]. The members of this superfamily share a structural motif of 10 TM segments that has been observed in crystal structures of the NSS bacterial homolog LeuTAa, a Na+-dependent amino acid transporter from Aquiflex aeolicus [7] and in several other transporter families structurally related to LeuT [4].
Further reading
* Key recommended reading is highlighted with an asterisk
Aragón C, López-Corcuera B. (2005) Glycine transporters: crucial roles of pharmacological interest revealed by gene deletion. Trends Pharmacol Sci, 26 (6): 283-6. [PMID:15925702]
* Bermingham DP, Blakely RD. (2016) Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters. Pharmacol Rev, 68 (4): 888-953. [PMID:27591044]
Betz H, Gomeza J, Armsen W, Scholze P, Eulenburg V. (2006) Glycine transporters: essential regulators of synaptic transmission. Biochem Soc Trans, 34 (Pt 1): 55-8. [PMID:16417482]
Bridges TM, Williams R, Lindsley CW. (2008) Design of potent GlyT1 inhibitors: in vitro and in vivo profiles. Curr Opin Mol Ther, 10 (6): 591-601. [PMID:19051137]
Bröer S. (2006) The SLC6 orphans are forming a family of amino acid transporters. Neurochem Int, 48 (6-7): 559-67. [PMID:16540203]
Bröer S. (2008) Apical transporters for neutral amino acids: physiology and pathophysiology. Physiology (Bethesda), 23: 95-103. [PMID:18400692]
* Bröer S, Gether U. (2012) The solute carrier 6 family of transporters. Br J Pharmacol, 167 (2): 256-78. [PMID:22519513]
Chen NH, Reith ME, Quick MW. (2004) Synaptic uptake and beyond: the sodium- and chloride-dependent neurotransmitter transporter family SLC6. Pflugers Arch, 447 (5): 519-31. [PMID:12719981]
Chiba P, Freissmuth M, Stockner T. (2014) Defining the blanks--pharmacochaperoning of SLC6 transporters and ABC transporters. Pharmacol Res, 83: 63-73. [PMID:24316454]
Christie DL. (2007) Functional insights into the creatine transporter. Subcell Biochem, 46: 99-118. [PMID:18652074]
Clausen RP, Madsen K, Larsson OM, Frølund B, Krogsgaard-Larsen P, Schousboe A. (2006) Structure-activity relationship and pharmacology of gamma-aminobutyric acid (GABA) transport inhibitors. Adv Pharmacol, 54: 265-84. [PMID:17175818]
* Colas C. (2020) Toward a Systematic Structural and Functional Annotation of Solute Carriers Transporters-Example of the SLC6 and SLC7 Families. Front Pharmacol, 11: 1229. [PMID:32973497]
Dai W, Vinnakota S, Qian X, Kunze DL, Sarkar HK. (1999) Molecular characterization of the human CRT-1 creatine transporter expressed in Xenopus oocytes. Arch Biochem Biophys, 361 (1): 75-84. [PMID:9882430]
Dalby NO. (2003) Inhibition of gamma-aminobutyric acid uptake: anatomy, physiology and effects against epileptic seizures. Eur J Pharmacol, 479 (1-3): 127-37. [PMID:14612144]
Daws LC. (2009) Unfaithful neurotransmitter transporters: focus on serotonin uptake and implications for antidepressant efficacy. Pharmacol Ther, 121 (1): 89-99. [PMID:19022290]
Dohi T, Morita K, Kitayama T, Motoyama N, Morioka N. (2009) Glycine transporter inhibitors as a novel drug discovery strategy for neuropathic pain. Pharmacol Ther, 123 (1): 54-79. [PMID:19393690]
Eulenburg V, Armsen W, Betz H, Gomeza J. (2005) Glycine transporters: essential regulators of neurotransmission. Trends Biochem Sci, 30 (6): 325-33. [PMID:15950877]
Foster JD, Cervinski MA, Gorentla BK, Vaughan RA. (2006) Regulation of the dopamine transporter by phosphorylation. Handb Exp Pharmacol, (175): 197-214. [PMID:16722237]
Gadea A, López-Colomé AM. (2001) Glial transporters for glutamate, glycine, and GABA: II. GABA transporters. J Neurosci Res, 63 (6): 461-8. [PMID:11241581]
Gasnier B. (2004) The SLC32 transporter, a key protein for the synaptic release of inhibitory amino acids. Pflugers Arch, 447 (5): 756-9. [PMID:12750892]
Gether U, Andersen PH, Larsson OM, Schousboe A. (2006) Neurotransmitter transporters: molecular function of important drug targets. Trends Pharmacol Sci, 27 (7): 375-83. [PMID:16762425]
Gomeza J, Armsen W, Betz H, Eulenburg V. (2006) Lessons from the knocked-out glycine transporters. Handb Exp Pharmacol, (175): 457-83. [PMID:16722246]
Gonzalez-Burgos G. (2010) GABA transporter GAT1: a crucial determinant of GABAB receptor activation in cortical circuits?. Adv Pharmacol, 58: 175-204. [PMID:20655483]
Han X, Patters AB, Jones DP, Zelikovic I, Chesney RW. (2006) The taurine transporter: mechanisms of regulation. Acta Physiol (Oxf), 187 (1-2): 61-73. [PMID:16734743]
Harsing LG, Juranyi Z, Gacsalyi I, Tapolcsanyi P, Czompa A, Matyus P. (2006) Glycine transporter type-1 and its inhibitors. Curr Med Chem, 13 (9): 1017-44. [PMID:16611082]
Harvey RJ, Topf M, Harvey K, Rees MI. (2008) The genetics of hyperekplexia: more than startle!. Trends Genet, 24 (9): 439-47. [PMID:18707791]
Harvey RJ, Yee BK. (2013) Glycine transporters as novel therapeutic targets in schizophrenia, alcohol dependence and pain. Nat Rev Drug Discov, 12 (11): 866-85. [PMID:24172334]
Hashimoto K. (2011) Glycine transporter-1: a new potential therapeutic target for schizophrenia. Curr Pharm Des, 17 (2): 112-20. [PMID:21355838]
Horstmann S, Binder EB. (2009) Pharmacogenomics of antidepressant drugs. Pharmacol Ther, 124 (1): 57-73. [PMID:19563827]
Høg S, Greenwood JR, Madsen KB, Larsson OM, Frølund B, Schousboe A, Krogsgaard-Larsen P, Clausen RP. (2006) Structure-activity relationships of selective GABA uptake inhibitors. Curr Top Med Chem, 6 (17): 1861-82. [PMID:17017962]
Javitt DC. (2009) Glycine transport inhibitors for the treatment of schizophrenia: symptom and disease modification. Curr Opin Drug Discov Devel, 12 (4): 468-78. [PMID:19562643]
* Joncquel-Chevalier Curt M, Voicu PM, Fontaine M, Dessein AF, Porchet N, Mention-Mulliez K, Dobbelaere D, Soto-Ares G, Cheillan D, Vamecq J. (2015) Creatine biosynthesis and transport in health and disease. Biochimie, 119: 146-65. [PMID:26542286]
Kanner BI. (2006) Structure and function of sodium-coupled GABA and glutamate transporters. J Membr Biol, 213 (2): 89-100. [PMID:17417704]
Karunakaran S, Umapathy NS, Thangaraju M, Hatanaka T, Itagaki S, Munn DH, Prasad PD, Ganapathy V. (2008) Interaction of tryptophan derivatives with SLC6A14 (ATB0,+) reveals the potential of the transporter as a drug target for cancer chemotherapy. Biochem J, 414 (3): 343-55. [PMID:18522536]
Kempson SA, Zhou Y, Danbolt NC. (2014) The betaine/GABA transporter and betaine: roles in brain, kidney, and liver. Front Physiol, 5: 159. [PMID:24795654]
Kristensen AS, Andersen J, Jørgensen TN, Sørensen L, Eriksen J, Loland CJ, Strømgaard K, Gether U. (2011) SLC6 neurotransmitter transporters: structure, function, and regulation. Pharmacol Rev, 63 (3): 585-640. [PMID:21752877]
Kulig K, Szwaczkiewicz M. (2008) The role of structure activity relationship studies in the search for new GABA uptake inhibitors. Mini Rev Med Chem, 8 (12): 1214-23. [PMID:18855736]
Lechner SM. (2006) Glutamate-based therapeutic approaches: inhibitors of glycine transport. Curr Opin Pharmacol, 6 (1): 75-81. [PMID:16376148]
* Lohr KM, Masoud ST, Salahpour A, Miller GW. (2017) Membrane transporters as mediators of synaptic dopamine dynamics: implications for disease. Eur J Neurosci, 45 (1): 20-33. [PMID:27520881]
Madsen KK, White HS, Schousboe A. (2010) Neuronal and non-neuronal GABA transporters as targets for antiepileptic drugs. Pharmacol Ther, 125 (3): 394-401. [PMID:20026354]
Mazei-Robinson MS, Blakely RD. (2006) ADHD and the dopamine transporter: are there reasons to pay attention?. Handb Exp Pharmacol, (175): 373-415. [PMID:16722244]
Millan MJ. (2006) Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application. Pharmacol Ther, 110 (2): 135-370. [PMID:16522330]
Moltzen EK, Bang-Andersen B. (2006) Serotonin reuptake inhibitors: the corner stone in treatment of depression for half a century--a medicinal chemistry survey. Curr Top Med Chem, 6 (17): 1801-23. [PMID:17017959]
Penmatsa A, Wang KH, Gouaux E. (2013) X-ray structure of dopamine transporter elucidates antidepressant mechanism. Nature, 503 (7474): 85-90. [PMID:24037379]
Ramamoorthy S, Shippenberg TS, Jayanthi LD. (2011) Regulation of monoamine transporters: Role of transporter phosphorylation. Pharmacol Ther, 129 (2): 220-38. [PMID:20951731]
Reynolds GP, McGowan OO, Dalton CF. (2014) Pharmacogenomics in psychiatry: the relevance of receptor and transporter polymorphisms. Br J Clin Pharmacol, 77 (4): 654-72. [PMID:24354796]
Richerson GB, Wu Y. (2004) Role of the GABA transporter in epilepsy. Adv Exp Med Biol, 548: 76-91. [PMID:15250587]
Rudnick G. (2011) Cytoplasmic permeation pathway of neurotransmitter transporters. Biochemistry, 50 (35): 7462-75. [PMID:21774491]
Rudnick G, Krämer R, Blakely RD, Murphy DL, Verrey F. (2014) The SLC6 transporters: perspectives on structure, functions, regulation, and models for transporter dysfunction. Pflugers Arch, 466 (1): 25-42. [PMID:24337881]
Runyon SP, Carroll FI. (2006) Dopamine transporter ligands: recent developments and therapeutic potential. Curr Top Med Chem, 6 (17): 1825-43. [PMID:17017960]
Saier MH, Yen MR, Noto K, Tamang DG, Elkan C. (2009) The Transporter Classification Database: recent advances. Nucleic Acids Res, 37 (Database issue): D274-8. [PMID:19022853]
Sarup A, Larsson OM, Schousboe A. (2003) GABA transporters and GABA-transaminase as drug targets. Curr Drug Targets CNS Neurol Disord, 2 (4): 269-77. [PMID:12871037]
Sałat K, Kulig K. (2011) GABA transporters as targets for new drugs. Future Med Chem, 3 (2): 211-22. [PMID:21428816]
Schousboe A, Madsen KK, White HS. (2011) GABA transport inhibitors and seizure protection: the past and future. Future Med Chem, 3 (2): 183-7. [PMID:21428813]
Schousboe A, Sarup A, Bak LK, Waagepetersen HS, Larsson OM. (2004) Role of astrocytic transport processes in glutamatergic and GABAergic neurotransmission. Neurochem Int, 45 (4): 521-7. [PMID:15186918]
Schousboe A, Sarup A, Larsson OM, White HS. (2004) GABA transporters as drug targets for modulation of GABAergic activity. Biochem Pharmacol, 68 (8): 1557-63. [PMID:15451399]
* Schumann-Gillett A, Blyth MT, O'Mara ML. (2019) Is protein structure enough? A review of the role of lipids in SLC6 transporter function. Neurosci Lett, 700: 64-69. [PMID:29758303]
Semyanov A, Walker MC, Kullmann DM, Silver RA. (2004) Tonically active GABA A receptors: modulating gain and maintaining the tone. Trends Neurosci, 27 (5): 262-9. [PMID:15111008]
Soudijn W, van Wijngaarden I. (2000) The GABA transporter and its inhibitors. Curr Med Chem, 7 (10): 1063-79. [PMID:10911018]
Supplisson S, Roux MJ. (2002) Why glycine transporters have different stoichiometries. FEBS Lett, 529 (1): 93-101. [PMID:12354619]
Sur C, Kinney GG. (2007) Glycine transporter 1 inhibitors and modulation of NMDA receptor-mediated excitatory neurotransmission. Curr Drug Targets, 8 (5): 643-9. [PMID:17504107]
Torres GE, Gainetdinov RR, Caron MG. (2003) Plasma membrane monoamine transporters: structure, regulation and function. Nat Rev Neurosci, 4 (1): 13-25. [PMID:12511858]
Vandenberg RJ, Ju P, Aubrey KR, Ryan RM, Mitrovic AD. (2004) Allosteric modulation of neurotransmitter transporters at excitatory synapses. Eur J Pharm Sci, 23 (1): 1-11. [PMID:15324920]
Vandenberg RJ, Ryan RM, Carland JE, Imlach WL, Christie MJ. (2014) Glycine transport inhibitors for the treatment of pain. Trends Pharmacol Sci, 35 (8): 423-30. [PMID:24962068]
Wang CI, Lewis RJ. (2010) Emerging structure-function relationships defining monoamine NSS transporter substrate and ligand affinity. Biochem Pharmacol, 79 (8): 1083-91. [PMID:19954741]
Williams JM, Galli A. (2006) The dopamine transporter: a vigilant border control for psychostimulant action. Handb Exp Pharmacol, (175): 215-32. [PMID:16722238]
Wolkenberg SE, Sur C. (2010) Recent progress in the discovery of non-sarcosine based GlyT1 inhibitors. Curr Top Med Chem, 10 (2): 170-86. [PMID:20166956]
Zafra F, Giménez C. (2008) Glycine transporters and synaptic function. IUBMB Life, 60 (12): 810-7. [PMID:18798526]
Zhong H, Sánchez C, Caron MG. (2012) Consideration of allosterism and interacting proteins in the physiological functions of the serotonin transporter. Biochem Pharmacol, 83 (4): 435-42. [PMID:21983034]
References
1. Alexander SPH, Kelly E, Mathie A, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Pawson AJ, Sharman JL et al.. (2019) THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Transporters. Br J Pharmacol, 176 Suppl 1: S397-S493. [PMID:31710713]
2. Bröer S. (2006) The SLC6 orphans are forming a family of amino acid transporters. Neurochem Int, 48 (6-7): 559-67. [PMID:16540203]
3. Chen NH, Reith ME, Quick MW. (2004) Synaptic uptake and beyond: the sodium- and chloride-dependent neurotransmitter transporter family SLC6. Pflugers Arch, 447 (5): 519-31. [PMID:12719981]
4. Forrest LR, Rudnick G. (2009) The rocking bundle: a mechanism for ion-coupled solute flux by symmetrical transporters. Physiology (Bethesda), 24: 377-86. [PMID:19996368]
5. Kristensen AS, Andersen J, Jørgensen TN, Sørensen L, Eriksen J, Loland CJ, Strømgaard K, Gether U. (2011) SLC6 neurotransmitter transporters: structure, function, and regulation. Pharmacol Rev, 63 (3): 585-640. [PMID:21752877]
6. Saier MH, Yen MR, Noto K, Tamang DG, Elkan C. (2009) The Transporter Classification Database: recent advances. Nucleic Acids Res, 37 (Database issue): D274-8. [PMID:19022853]
7. Yamashita A, Singh SK, Kawate T, Jin Y, Gouaux E. (2005) Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters. Nature, 437 (7056): 215-23. [PMID:16041361]
How to cite this family page
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Kelly E, Mathie A, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators. (2019) The Concise Guide to PHARMACOLOGY 2019/20: Transporters. Br J Pharmacol. 176 Issue S1: S397-S493.
