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Targeting Trafficking in Drug Development pp 249–270Cite as

SLC6 Transporter Folding Diseases and Pharmacochaperoning

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Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 245))

Abstract

The human genome encodes 19 genes of the solute carrier 6 (SLC6) family; non-synonymous changes in the coding sequence give rise to mutated transporters, which are misfolded and thus cause diseases in the affected individuals. Prominent examples include mutations in the transporters for dopamine (DAT, SLC6A3), for creatine (CT1, SLC6A8), and for glycine (GlyT2, SLC6A5), which result in infantile dystonia, mental retardation, and hyperekplexia, respectively. Thus, there is an obvious unmet medical need to identify compounds, which can remedy the folding deficit. The pharmacological correction of folding defects was originally explored in mutants of the serotonin transporter (SERT, SLC6A4), which were created to study the COPII-dependent export from the endoplasmic reticulum. This led to the serendipitous discovery of the pharmacochaperoning action of ibogaine. Ibogaine and its metabolite noribogaine also rescue several disease-relevant mutants of DAT. Because the pharmacology of DAT and SERT is exceptionally rich, it is not surprising that additional compounds have been identified, which rescue folding-deficient mutants. These compounds are not only of interest for restoring DAT function in the affected children. They are also likely to serve as useful tools to interrogate the folding trajectory of the transporter. This is likely to initiate a virtuous cycle: if the principles underlying folding of SLC6 transporters are understood, the design of pharmacochaperones ought to be facilitated.

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References

  • Alfadhel M, Nashabat M, Qahtani HA, Alfares A, Mutairi FA, Shaalan HA, Douglas GV, Wierenga K, Juusola J, Alrifai MT, Arold ST, Alkuraya F, Ali QA (2016) Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans. Hum Genet 135:1263–1268

    Article  CAS  Google Scholar 

  • Anderluh A, Klotzsch E, Ries J, Reismann AW, Weber S, Fölser M, Koban F, Freissmuth M, Sitte HH, Schütz GJ (2014) Tracking single serotonin transporter molecules at the endoplasmic reticulum and plasma membrane. Biophys J 106:L33–L35

    Article  CAS  Google Scholar 

  • Anderluh A, Hofmaier T, Klotzsch E, Kudlacek O, Stockner T, Sitte HH, Schütz GJ (2017) Direct PIP2 binding mediates stable oligomer formation of the serotonin transporter. Nat Commun 8:14089

    Article  CAS  Google Scholar 

  • Anfinsen CB (1973) Principles that govern the folding of protein chains. Science 181:223–230

    Article  CAS  Google Scholar 

  • Ardon O, Procter M, Mao R, Longo N, Landau YE, Shilon-Hadass A, Gabis LV, Hoffmann C, Tzadok M, Heimer G, Sada S, Ben-Zeev B, Anikster Y (2016) Creatine transporter deficiency: novel mutations and functional studies. Mol Genet Metab Rep 8:20–23

    Article  CAS  Google Scholar 

  • Arribas-González E, de Juan-Sanz J, Aragón C, López-Corcuera B (2015) Molecular basis of the dominant negative effect of a glycine transporter 2 mutation associated with hyperekplexia. J Biol Chem 290:2150–2165

    Article  Google Scholar 

  • Asjad HMM, Kasture A, El-Kasaby A, Sackel M, Hummel T, Freissmuth M, Sucic S (2017) Pharmacochaperoning in a Drosophila model system rescues human dopamine transporter variants associated with infantile/juvenile parkinsonism. J Biol Chem. In Press (Epub ahead of print Sept 29 2017; bc.M117.797092. doi:https://doi.org/10.1074/jbc.M117.797092)

    Article  PubMed  PubMed Central  Google Scholar 

  • Beerepoot P, Lam VM, Salahpour A (2016) Pharmacological chaperones of the dopamine transporter rescue dopamine transporter deficiency syndrome mutations in heterologous cells. J Biol Chem 291:22053–22062

    Article  CAS  Google Scholar 

  • Ben-Yona A, Kanner BI (2013) Functional defects in the external and internal thin gates of the γ-aminobutyric acid (GABA) transporter GAT-1 can compensate each other. J Biol Chem 288:4549–4556

    Article  CAS  Google Scholar 

  • Bhat S, Hasenhuetl PS, Kasture A, El-Kasaby A, Baumann MH, Blough BE, Sucic S, Sandtner W, Freissmuth M (2017) Conformational state interactions pro-vide clues to the pharmacochaperone potential of serotonin transporter partial sub-strates. J Biol Chem 292:16773–16786

    Article  CAS  Google Scholar 

  • Bröer S (2009) The role of the neutral amino acid transporter B0AT1 (SLC6A19) in Hartnup disorder and protein nutrition. IUBMB Life 61:591–599

    Article  Google Scholar 

  • Bröer S, Bailey CG, Kowalczuk S, Ng C, Vanslambrouck JM, Rodgers H, Auray-Blais C, Cavanaugh JA, Bröer A, Rasko JE (2008) Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters. J Clin Invest 118:3881–3892

    Article  Google Scholar 

  • Bröer S, Gether U (2012) The solute carrier 6 family of transporters. Br J Pharmacol 167:256–278

    Article  Google Scholar 

  • Bulling S, Schicker K, Zhang YW, Steinkellner T, Stockner T, Gruber CW, Boehm S, Freissmuth M, Rudnick G, Sitte HH, Sandtner W (2012) The mechanistic basis for noncompetitive ibogaine inhibition of serotonin and dopamine transporters. J Biol Chem 287:18524–18534

    Article  CAS  Google Scholar 

  • Camargo SM, Singer D, Makrides V, Huggel K, Pos KM, Wagner CA, Kuba K, Danilczyk U, Skovby F, Kleta R, Penninger JM, Verrey F (2009) Tissue-specific amino acid transporter partners ACE2 and collectrin differentially interact with Hartnup mutations. Gastroenterology 136:872–882

    Article  CAS  Google Scholar 

  • Carta E, Chung SK, James VM, Robinson A, Gill JL, Remy N, Vanbellinghen JF, Drew CJ, Cagdas S, Cameron D, Cowan FM, Del Toro M, Graham GE, Manzur AY, Masri A, Rivera S, Scalais E, Shiang R, Sinclair K, Stuart CA, Tijssen MA, Wise G, Zuberi SM, Harvey K, Pearce BR, Topf M, Thomas RH, Supplisson S, Rees MI, Harvey RJ (2012) Mutations in the GlyT2 gene (SLC6A5) are a second major cause of startle disease. J Biol Chem 287:28975–28985

    Article  CAS  Google Scholar 

  • Carvill GL, McMahon JM, Schneider A, Zemel M, Myers CT, Saykally J, Nguyen J, Robbiano A, Zara F, Specchio N, Mecarelli O, Smith RL, Leventer RJ, Møller RS, Nikanorova M, Dimova P, Jordanova A, Petrou S, EuroEPINOMICS Rare Epilepsy Syndrome Myoclonic-Astatic Epilepsy & Dravet Working Group, Helbig I, Striano P, Weckhuysen S, Berkovic SF, Scheffer IE, Mefford HC (2015) Mutations in the GABA transporter SLC6A1 cause epilepsy with myoclonic-atonic seizures. Am J Hum Genet 96:808–815

    Article  CAS  Google Scholar 

  • Cheon CK, Lee BH, Ko JM, Kim HJ, Yoo HW (2010) Novel mutation in SLC6A19 causing late-onset seizures in Hartnup disorder. Pediatr Neurol 42:369–371

    Article  Google Scholar 

  • Chiba P, Freissmuth M, Stockner T (2014) Defining the blanks–pharmacochaperoning of SLC6 transporters and ABC transporters. Pharmacol Res 83:63–73

    Article  CAS  Google Scholar 

  • Chiu CS, Brickley S, Jensen K, Southwell A, Mckinney S, Cull-Candy S, Mody I, Lester HA (2005) GABA transporter deficiency causes tremor, ataxia, nervousness, and increased GABA-induced tonic conductance in cerebellum. J Neurosci 25:3234–3245

    Article  CAS  Google Scholar 

  • Coleman JA, Green EM, Gouaux E (2016) X-ray structures and mechanism of the human serotonin transporter. Nature 532:334–339

    Article  CAS  Google Scholar 

  • Cope DW, Di Giovanni G, Fyson SJ, Orbán G, Errington AC, Lorincz ML, Gould TM, Carter DA, Crunelli V (2009) Enhanced tonic GABAA inhibition in typical absence epilepsy. Nat Med 15:1392–1398

    Article  CAS  Google Scholar 

  • Cymer F, von Heijne G, White SH (2015) Mechanisms of integral membrane protein insertion and folding. J Mol Biol 427:999–1022

    Article  CAS  Google Scholar 

  • DesRoches CL, Patel J, Wang P, Minassian B, Salomons GS, Marshall CR, Mercimek-Mahmutoglu S (2015) Estimated carrier frequency of creatine transporter deficiency in females in the general population using functional characterization of novel missense variants in the SLC6A8 gene. Gene 565:187–191

    Article  CAS  Google Scholar 

  • Dikow N, Maas B, Karch S, Granzow M, Janssen JW, Jauch A, Hinderhofer K, Sutter C, Schubert-Bast S, Anderlid BM, Dallapiccola B, Van der Aa N, Moog U (2014) 3p25.3 microdeletion of GABA transporters SLC6A1 and SLC6A11 results in intellectual disability, epilepsy and stereotypic behavior. Am J Med Genet A 164:3061–3068

    Article  CAS  Google Scholar 

  • Dill KA, MacCallum J (2012) The protein-folding problem, 50 years on. Science 338:1042–1046

    Article  CAS  Google Scholar 

  • El-Kasaby A, Just H, Malle E, Stolt-Bergner PC, Sitte HH, Freissmuth M, Kudlacek O (2010) Mutations in the carboxyl-terminal SEC24 binding motif of the serotonin transporter impair folding of the transporter. J Biol Chem 285:39201–39210

    Article  CAS  Google Scholar 

  • El-Kasaby A, Koban F, Sitte HH, Freissmuth M, Sucic S (2014) A cytosolic relay of heat shock proteins HSP70–1A and HSP90β monitors the folding trajectory of the serotonin transporter. J Biol Chem 289:28987–29000

    Article  CAS  Google Scholar 

  • Eulenburg V, Becker K, Gomeza J, Schmitt B, Becker CM, Betz H (2006) Mutations within the human GLYT2 (SLC6A5) gene associated with hyperekplexia. Biochem Biophys Res Commun 348:400–405

    Article  CAS  Google Scholar 

  • Fairweather SJ, Bröer A, Subramanian N, Tumer E, Cheng Q, Schmoll D, O'Mara ML, Bröer S (2015) Molecular basis for the interaction of the mammalian amino acid transporters B0AT1 and B0AT3 with their ancillary protein collectrin. J Biol Chem 290:24308–24325

    Article  CAS  Google Scholar 

  • Farhan H, Korkhov VM, Paulitschke V, Dorostkar MM, Scholze P, Kudlacek O, Freissmuth M, Sitte HH (2004) Two discontinuous segments in the carboxyl terminus are required for membrane targeting of the rat gamma-aminobutyric acid transporter-1 (GAT1). J Biol Chem 279:28553–28563

    Article  CAS  Google Scholar 

  • Farhan H, Freissmuth M, Sitte HH (2006) Oligomerization of neurotransmitter transporters: a ticket from the endoplasmic reticulum to the plasma membrane. Handb Exp Pharmacol 175:233–249

    Article  CAS  Google Scholar 

  • Farhan H, Reiterer V, Korkhov VM, Schmid JA, Freissmuth M, Sitte HH (2007) Concentrative export from the endoplasmic reticulum of the γ-aminobutyric acid transporter 1 requires binding to SEC24D. J Biol Chem 282:7679–7689

    Article  CAS  Google Scholar 

  • Fujiwara M, Yamamoto H, Miyagi T, Seki T, Tanaka S, Hide I, Sakai N (2013) Effects of the chemical chaperone 4-phenylbutylate on the function of the serotonin transporter (SERT) expressed in COS-7 cells. J Pharmacol Sci 122:71–83

    Article  CAS  Google Scholar 

  • Giménez C, Pérez-Siles G, Martínez-Villarreal J, Arribas-González E, Jiménez E, Núñez E, de Juan-Sanz J, Fernández-Sánchez E, García-Tardón N, Ibáñez I, Romanelli V, Nevado J, James VM, Topf M, Chung SK, Thomas RH, Desviat LR, Aragón C, Zafra F, Rees MI, Lapunzina P, Harvey RJ, López-Corcuera B (2012) A novel dominant hyperekplexia mutation Y705C alters trafficking and biochemical properties of the presynaptic glycine transporterGlyT2. J Biol Chem 287:28986–29002

    Article  Google Scholar 

  • Hahn MK, Robertson D, Blakely RD (2003) A mutation in the human norepinephrine transporter gene (SLC6A2) associated with orthostatic intolerance disrupts surface expression of mutant and wild-type transporters. J Neurosci 23:4470–4478

    Article  CAS  Google Scholar 

  • Hansen FH, Skjørringe T, Yasmeen S, Arends NV, Sahai MA, Erreger K, Andreassen TF, Holy M, Hamilton PJ, Neergheen V, Karlsborg M, Newman AH, Pope S, Heales SJ, Friberg L, Law I, Pinborg LH, Sitte HH, Loland C, Shi L, Weinstein H, Galli A, Hjermind LE, Møller LB, Gether U (2014) Missense dopamine transporter mutations associate with adult parkinsonism and ADHD. J Clin Invest 124:3107–3120

    Article  CAS  Google Scholar 

  • Hasenhuetl PS, Freissmuth M, Sandtner W (2016) Electrogenic binding of intracellular cations defines a kinetic decision-point in the transport cycle of SERT. J Biol Chem 291:25864–25876

    Article  CAS  Google Scholar 

  • Jacobs MT, Zhang YW, Campbell SD, Rudnick G (2007) Ibogaine, a noncompetitive inhibitor of serotonin transport, acts by stabilizing the cytoplasm-facing state of the transporter. J Biol Chem 282:29441–29447

    Article  CAS  Google Scholar 

  • Janowsky A, Tosh DK, Eshleman AJ, Jacobson KA (2016) Rigid adenine nucleoside derivatives as novel modulators of the human sodium symporters for dopamine and norepinephrine. J Pharmacol Exp Ther 357:24–35

    Article  CAS  Google Scholar 

  • Just H, Sitte HH, Schmid JA, Freissmuth M, Kudlacek O (2004) Identification of an additional interaction domain in transmembrane domains 11 and 12 that supports oligomer formation in the human serotonin transporter. J Biol Chem 279:6650–6657

    Article  CAS  Google Scholar 

  • van de Kamp JM, Betsalel OT, Mercimek-Mahmutoglu S, Abulhoul L, Grünewald S, Anselm I, Azzouz H, Bratkovic D, de Brouwer A, Hamel B, Kleefstra T, Yntema H, Campistol J, Vilaseca MA, Cheillan D, D'Hooghe M, Diogo L, Garcia P, Valongo C, Fonseca M, Frints S, Wilcken B, von der Haar S, Meijers-Heijboer HE, Hofstede F, Johnson D, Kant SG, Lion-Francois L, Pitelet G, Longo N, Maat-Kievit JA, Monteiro JP, Munnich A, Muntau AC, Nassogne MC, Osaka H, Ounap K, Pinard JM, Quijano-Roy S, Poggenburg I, Poplawski N, Abdul-Rahman O, Ribes A, Arias A, Yaplito-Lee J, Schulze A, Schwartz CE, Schwenger S, Soares G, Sznajer Y, Valayannopoulos V, Van Esch H, Waltz S, Wamelink MM, Pouwels PJ, Errami A, van der Knaap MS, Jakobs C, Mancini GM, Salomons GS (2013) Phenotype and genotype in 101 males with X-linked creatine transporter deficiency. J Med Genet 50:463–472

    Article  Google Scholar 

  • van de Kamp JM, Mancini GM, Salomons GS (2014) X-linked creatine transporter deficiency: clinical aspects and pathophysiology. J Inherit Metab Dis 37:715–733

    Article  Google Scholar 

  • Kasture A, El-Kasaby A, Szöllösi D, Asjad HMM, Grimm A, Stockner T, Hummel T, Freissmuth M, Sucic S (2016) Functional rescue of a misfolded Drosophila melanogaster dopamine transporter mutant associated with a sleepless phenotype by pharmacological chaperones. J Biol Chem 291:20876–20890

    Article  CAS  Google Scholar 

  • Kasture A, Stockner T, Freissmuth M, Sucic S (2017) An unfolding story: Small molecules remedy misfolded monoamine transporters. Int J Biochem Cell Biol 92:1–5

    Article  CAS  Google Scholar 

  • Kern C, Erdem FA, El-Kasaby A, Sandtner W, Freissmuth M, Sucic S (2017) The N terminus specifies the switch between transport modes of the human serotonin transporter. J Biol Chem 292:3603–3613

    Article  CAS  Google Scholar 

  • Koban F, El-Kasaby A, Häusler C, Stockner T, Simbrunner BM, Sitte HH, Freissmuth M, Sucic S (2015) A salt bridge linking the first intracellular loop with the C terminus facilitates the folding of the serotonin transporter. J Biol Chem 290:13263–13278

    Article  CAS  Google Scholar 

  • Korkhov VM, Farhan H, Freissmuth M, Sitte HH (2004) Oligomerization of the γ-aminobutyric acid transporter-1 is driven by an interplay of polar and hydrophobic interactions in transmembrane helix II. J Biol Chem 279:55728–55736

    Article  CAS  Google Scholar 

  • Korkhov VM, Holy M, Freissmuth M, Sitte HH (2006) The conserved glutamate (Glu136) in transmembrane domain 2 of the serotonin transporter is required for the conformational switch in the transport cycle. J Biol Chem 281:13439–13448

    Article  CAS  Google Scholar 

  • Korkhov VM, Milan-Lobo L, Zuber B, Farhan H, Schmid JA, Freissmuth M, Sitte HH (2008) Peptide-based interactions with calnexin target misassembled membrane proteins into endoplasmic reticulum-derived multilamellar bodies. J Mol Biol 378:337–352

    Article  CAS  Google Scholar 

  • Kowalczuk S, Bröer A, Tietze N, Vanslambrouck JM, Rasko JE, Bröer S (2008) A protein complex in the brush-border membrane explains a Hartnup disorder allele. FASEB J 22:2880–2887

    Article  CAS  Google Scholar 

  • Kume K, Kume S, Park SK, Hirsh J, Jackson FR (2005) Dopamine is a regulator of arousal in the fruit fly. J Neurosci 25:7377–7384

    Article  CAS  Google Scholar 

  • Kurian MA, Zhen J, Cheng SY, Li Y, Mordekar SR, Jardine P, Morgan NV, Meyer E, Tee L, Pasha S, Wassmer E, Heales SJ, Gissen P, Reith ME, Maher ER (2009) Homozygous loss-of-function mutations in the gene encoding the dopamine transporter are associated with infantile parkinsonism-dystonia. J Clin Invest 11:1595–1603

    Google Scholar 

  • Kurian MA, Li Y, Zhen J, Meyer E, Hai N, Christen HJ, Hoffmann GF, Jardine P, von Moers A, Mordekar SR, O’Callaghan F, Wassmer E, Wraige E, Dietrich C, Lewis T, Hyland K, Heales S Jr, Sanger T, Gissen P, Assmann BE, Reith ME, Maher ER (2011) Clinical and molecular characterisation of hereditary dopamine transporter deficiency syndrome: an observational cohort and experimental study. Lancet Neurol 10:54–62

    Article  CAS  Google Scholar 

  • Kurolap A, Armbruster A, Hershkovitz T, Hauf K, Mory A, Paperna T, Hannappel E, Tal G, Nijem Y, Sella E, Mahajnah M, Ilivitzki A, Hershkovitz D, Ekhilevitch N, Mandel H, Eulenburg V, Baris HN (2016) Loss of glycine transporter 1 causes a subtype of glycine encephalopathy with arthrogryposis and mildly elevated cerebrospinal fluid glycine. Am J Hum Genet 99:1172–1180

    Article  CAS  Google Scholar 

  • Kusek J, Yang Q, Witek M, Gruber CW, Nanoff C, Freissmuth M (2015) Chaperoning of the A1-adenosine receptor by endogenous adenosine – an extension of the retaliatory metabolite concept. Mol Pharmacol 87:39–51

    Article  Google Scholar 

  • Larsen MB, Fjorback AW, Wiborg O (2006) The C-terminus is critical for the functional expression of the human serotonin transporter. Biochemistry 45:1331–1337

    Article  CAS  Google Scholar 

  • Levinthal C (1969) How to fold graciously. In: DeBrunner JTP, Munck E (eds) Mössbauer spectroscopy in biological systems. University of Illinois Press, Allerton House, Monticello, IL, pp 22–24

    Google Scholar 

  • Li Y, Hasenhuetl PS, Schicker K, Sitte HH, Freissmuth M, Sandtner W (2015) Dual action of Zn2+ on the transport cycle of the dopamine transporter. J Biol Chem 290:31069–31076

    Article  CAS  Google Scholar 

  • Li Y, Mayer FP, Hasenhuetl PS, Burtscher V, Schicker K, Sitte HH, Freissmuth M, Sandtner W (2017) Occupancy of the zinc-binding site by transition metals decreases the substrate affinity of the human dopamine transporter by an allosteric mechanism. J Biol Chem 292:4235–4243

    Article  CAS  Google Scholar 

  • Löscher W (2011) Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure 20:359–368

    Article  Google Scholar 

  • Ma W, Goldberg E, Goldberg J (2017) ER retention is imposed by COPII protein sorting and attenuated by 4-phenylbutyrate. Elife 6:e26624

    PubMed  PubMed Central  Google Scholar 

  • Mantoan L, Walker M (2011) Treatment options in juvenile myoclonic epilepsy. Curr Treat Options Neurol 13:355–370

    Article  Google Scholar 

  • Masri A, Chung SK, Rees MI (2017) Hyperekplexia: report on phenotype and genotype of 16 Jordanian patients. Brain Dev 39:306–311

    Article  Google Scholar 

  • Ng J, Zhen J, Meyer E, Erreger K, Li Y, Kakar N, Ahmad J, Thiele H, Kubisch C, Rider NL, Morton DH, Strauss KA, Puffenberger EG, D'Agnano D, Anikster Y, Carducci C, Hyland K, Rotstein M, Leuzzi V, Borck G, Reith ME, Kurian MA (2014) Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood. Brain 137:1107–1119

    Article  Google Scholar 

  • Palmer S, Towne MC, Pearl PL, Pelletier RC, Genetti CA, Shi J, Beggs AH, Agrawal PB, Brownstein CA (2016) SLC6A1 mutation and ketogenic diet in epilepsy with myoclonic-atonic seizures. Pediatr Neurol 64:77–79

    Article  Google Scholar 

  • Parra LA, Baust T, El Mestikawy S, Quiroz M, Hoffman B, Haflett JM, Yao JK, Torres GE (2008) The orphan transporter Rxt1/NTT4 (SLC6A17) functions as a synaptic vesicle amino acid transporter selective for proline, glycine, leucine, and alanine. Mol Pharmacol 74:1521–1523

    Article  CAS  Google Scholar 

  • Penmatsa A, Wang KH, Gouaux E (2013) X-ray structure of dopamine transporter elucidates antidepressant mechanism. Nature 503:85–90

    Article  CAS  Google Scholar 

  • Rees MI, Harvey K, Pearce BR, Chung SK, Duguid IC, Thomas P, Beatty S, Graham GE, Armstrong L, Shiang R, Abbott KJ, Zuberi SM, Stephenson JB, Owen MJ, Tijssen MA, van den Maagdenberg AM, Smart TG, Supplisson S, Harvey RJ (2006) Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease. Nat Genet 38:801–806

    Article  CAS  Google Scholar 

  • Rosenberg A, Kanner BI (2008) The substrates of the γ-aminobutyric acid transporter GAT-1 induce structural rearrangements around the interface of transmembrane domains 1 and 6. J Biol Chem 283:14376–14383

    Article  CAS  Google Scholar 

  • Rubenstein RC, Zeitlin PL (2000) Sodium 4-phenylbutyrate downregulates Hsc70: implications for intracellular trafficking of ΔF508-CFTR. Am J Physiol Cell Physiol 278:C259–C267

    Article  CAS  Google Scholar 

  • Schmid JA, Scholze P, Kudlacek O, Freissmuth M, Singer EA, Sitte HH (2001) Oligomerization of the human serotonin transporter and of the rat GABA transporter 1 visualized by fluorescence resonance energy transfermicroscopy in living cells. J Biol Chem 276:3805–3810

    Article  CAS  Google Scholar 

  • Scholze P, Freissmuth M, Sitte HH (2002) Mutations within an intramembrane leucine heptad repeat disrupt oligomer formation of the rat GABA transporter 1. J Biol Chem 277:43682–43690

    Article  CAS  Google Scholar 

  • Seyer P, Vandermoere F, Cassier E, Bockaert J, Marin P (2016) Physical and functional interactions between the serotonin transporter and the neutral amino acid transporter ASCT2. Biochem J 473:1953–1965

    Article  CAS  Google Scholar 

  • Shannon JR, Flattem NL, Jordan J, Jacob G, Black BK, Biaggioni I, Blakely RD, Robertson D (2000) Clues to the origin of orthostatic intolerance: a genetic defect in the cocaine- and antidepressant-sensitive norepinephrine transporter. N Engl J Med 342:541–549

    Article  CAS  Google Scholar 

  • Shen MY, Sali A (2006) Statistical potential for assessment and prediction of protein structures. Protein Sci 15:2507–2524

    Article  CAS  Google Scholar 

  • Singer D, Camargo SM, Huggel K, Romeo E, Danilczyk U, Kuba K, Chesnov S, Caron MG, Penninger JM, Verrey F (2009) Orphan transporter SLC6A18 is renal neutral amino acid transporter B0AT3. J Biol Chem 284:19953–19960

    Article  CAS  Google Scholar 

  • Sitte HH, Freissmuth M (2015) Amphetamines, new psychoactive drugs and the monoamine transporter cycle. Trends Pharmacol Sci 36:41–50

    Article  CAS  Google Scholar 

  • Stockner T, Montgomery TR, Kudlacek O, Weissensteiner R, Ecker GF, Freissmuth M, Sitte HH (2013) Mutational analysis of the high-affinity zinc binding site validates a refined human dopamine transporter homology model. PLoS Comput Biol 9:e1002909

    Article  CAS  Google Scholar 

  • Sucic S, Bryan-Lluka LJ (2005) Roles of transmembrane domain 2 and the first intracellular loop in human noradrenaline transporter function: pharmacological and SCAM analysis. J Neurochem 94:1620–1630

    Article  CAS  Google Scholar 

  • Sucic S, Bryan-Lluka LJ (2007) Investigation of the functional roles of the MELAL and GQXXRXG motifs of the human noradrenaline transporter using cysteine mutants. Eur J Pharmacol 556:27–35

    Article  CAS  Google Scholar 

  • Sucic S, Dallinger S, Zdrazil B, Weissensteiner R, Jørgensen TN, Holy M, Kudlacek O, Seidel S, Cha JH, Gether U, Newman AH, Ecker GF, Freissmuth M, Sitte HH (2010) The N terminus of monoamine transporters is a lever required for the action of amphetamines. J Biol Chem 285:10924–10938

    Article  CAS  Google Scholar 

  • Sucic S, El-Kasaby A, Kudlacek O, Sarker S, Sitte HH, Marin P, Freissmuth M (2011) The serotonin transporter is an exclusive client of the coat protein complex II (COPII) component SEC24C. J Biol Chem 286:16482–16490

    Article  CAS  Google Scholar 

  • Sucic S, Koban F, El-Kasaby A, Kudlacek O, Stockner T, Sitte HH, Freissmuth M (2013) Switching the clientele: a lysine residing in the C terminus of the serotonin transporter specifies its preference for the coat protein complex II component SEC24C. J Biol Chem 288:5330–5341

    Article  CAS  Google Scholar 

  • Swistowski A, Peng J, Liu Q, Mali P, Rao MS, Cheng L, Zeng X (2010) Efficient generation of functional dopaminergic neurons from human induced pluripotent stem cells under defined conditions. Stem Cells 28:1893–1904

    Article  CAS  Google Scholar 

  • Uemura T, Ito S, Ohta Y, Tachikawa M, Wada T, Terasaki T, Ohtsuki S (2017) Abnormal N-glycosylation of a novel missense creatine transporter mutant, G561R, associated with cerebral creatine deficiency syndromes alters transporter activity and localization. Biol Pharm Bull 40:49–55

    Article  CAS  Google Scholar 

  • Zaia KA, Reimer RJ (2009) Synaptic vesicle protein NTT4/XT1 (SLC6A17) catalyzes Na+-coupled neutral amino acid transport. J Biol Chem 284:8439–8448

    Article  CAS  Google Scholar 

  • Zanetti G, Pahuja KB, Studer S, Shim S, Schekman R (2011) COPII and the regulation of protein sorting in mammals. Nat Cell Biol 14:20–28

    Article  Google Scholar 

  • Zech M, Jech R, Wagner M, Mantel T, Boesch S, Nocker M, Jochim A, Berutti R, Havránková P, Fečíková A, Kemlink D, Roth J, Strom TM, Poewe W, Růžička E, Haslinger B, Winkelmann J (2017) Molecular diversity of combined and complex dystonia: insights from diagnostic exome sequencing. Neurogenetics. In Press (published online Aug 28 2017. doi:https://doi.org/10.1007/s10048-017-0521-9)https://doi.org/10.1007/s10048-017-0521-9)

  • Zheng Y, Zhou C, Huang Y, Bu D, Zhu X, Jiang W (2009) A novel missense mutation in the SLC6A19 gene in a Chinese family with Hartnup disorder. Int J Dermatol 48:388–392

    Article  CAS  Google Scholar 

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Acknowledgments

Work from the authors’ laboratory was supported by grants from the Austrian Science Fund/FWF (SFB35-10, SFB35-24, and P27518-B27). We are grateful to Nikola Freissmuth for her excellent support with preparing the graphical illustrations.

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Authors and Affiliations

  1. Institute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

    Michael Freissmuth, Thomas Stockner & Sonja Sucic

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  1. Michael Freissmuth
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  2. Thomas Stockner
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  3. Sonja Sucic
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Correspondence to Michael Freissmuth .

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Editors and Affiliations

  1. Red de Apoyo a la Investigación, National Autonomous University of Mexico and Instituto Nacional de Ciencias, Médicas y Nutrición SZ, Mexico City, Mexico

    Alfredo Ulloa-Aguirre

  2. Dep of Anatomy, Physiology and Pharmacology, Auburn University, College of Veterinary Medicine, Auburn, Alabama, USA

    Ya-Xiong Tao

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Freissmuth, M., Stockner, T., Sucic, S. (2017). SLC6 Transporter Folding Diseases and Pharmacochaperoning. In: Ulloa-Aguirre, A., Tao, YX. (eds) Targeting Trafficking in Drug Development. Handbook of Experimental Pharmacology, vol 245. Springer, Cham. https://doi.org/10.1007/164_2017_71

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