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Gene Review

SLC6A4  -  solute carrier family 6 (neurotransmitter...

Homo sapiens

Synonyms: 5-HTT, 5-HTTLPR, 5HT transporter, 5HTT, HTT, ...

Disease relevance of SLC6A4


Psychiatry related information on SLC6A4

  1. SLC6A4 and the Development of Aggressive Behaviors: The short variant of the serotonin transporter promoter gene has been found to positively correlate with aggressive behavior in a general sample of middle school children [6]. It has also been linked to aggressive conducts in the presence of attention deficit disorder in males [7], and with impulsive violent behavior in early onset alcoholism.
  2. Other associations:
  • Previous studies have yielded conflicting results as to the putative role of the functional polymorphism of the promoter region of the serotonin transporter gene (SLC6A4) in the etiology of anxiety-related traits and depressive disorders [2].
  • Six previous family-based association studies of SLC6A4 in autistic disorder have been conducted, with four studies showing nominally significant transmission disequilibrium and two studies with no evidence of nominally significant transmission disequilibrium [8].
  • Current studies have found associations of SLC6A4 polymorphisms with several psychiatric traits including bipolar affective disorder (BPD) in various populations; however, studies with contradictory results were also reported [9].
  • Weight-restored patients with anorexia nervosa (AN) respond favorably to the selective serotonin reuptake inhibitor fluoxetine, which justifies association studies of the serotonin transporter gene (SLC6A4, alias SERT) and AN [10].
  • The 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4) may contribute to the risk of bipolar disorder, suicidal behavior, and neuroticism, but association to the lifetime risk of major depression has not been shown [11].
  • In patients with mood disorders, we found significant difference in mean 5-HIAA concentration between 5-HTTLPR genotypes (p=0.03) [12].

High impact information on SLC6A4

  • We screened for variants in the complete coding sequence and intron-exon junctions of two candidate genes for neuropsychiatric phenotypes: SLC6A4, encoding the serotonin transporter; and SLC18A2, encoding the vesicular monoamine transporter [13].
  • Phosphorylation and sequestration of the serotonin transporter (SERT) were substantially impacted by ligand occupancy [14].
  • Human 5-HT transporter (5-HTT) gene transcription is modulated by a common polymorphism in its upstream regulatory region [15].
  • The Silastic device, dubbed SERT (sustained ethanol release tube), holds 0.35 milliliter of 95 percent ethanol (by volume) and is implanted under the skin of the back where it releases ethanol for up to 12 hours, with no observable tissue damage [16].
  • These transporters for dopamine (DAT), serotonin (SERT), and norepinephrine (NET), which are expressed selectively on the corresponding neurons, are established targets of many psychostimulants, antidepressants, and neurotoxins [17].

Chemical compound and disease context of SLC6A4


Biological context of SLC6A4

  • In particular, two common alleles in a variable repeat sequence of the promoter region (SLC6A4) have been differentially associated with a display of abnormal levels of anxiety and affective illness in individuals carrying the "s" allele [20].
  • Frontal and limbic metabolic differences in subjects selected according to genetic variation of the SLC6A4 gene polymorphism [20].
  • There was no effect of SLC6A4 genotype upon serotonin transporter binding [21].
  • To further elucidate the putative association between the two SLC6A4 gene polymorphisms and schizophrenia susceptibility, we performed a meta-analysis based on all original published association studies between schizophrenia and the 5-HTTLPR and STin2 VNTR polymorphisms published before April 2004 [22].
  • Two functional polymorphisms within the serotonin transporter (SLC6A4) gene (promoter 44 bp insertion/deletion (HTTLPR) and an intron two 16 or 17 bp variable number tandem repeat (VNTR2)) have been extensively studied in psychiatric conditions but not in the cognitive functioning of normal individuals [23].

Anatomical context of SLC6A4


Associations of SLC6A4 with chemical compounds

  • Our most intriguing result involved three SNPs in the TPH1 gene and one SNP in the SLC6A4 gene, which show significant single-locus association when response to fluoxetine is compared to nonresponse (P=0.02-0.04) [28].
  • In the present 12-week follow-up study, the combined effect of HTR1A and SLC6A4 genes in clinical outcome and response to citalopram was also evaluated [29].
  • Because of an interaction between the serotonin (5-HT) and DA systems, the serotonin transporter gene (SLC6A4) has been considered as a candidate ADHD susceptibility gene [30].
  • From this series, the dimethylated derivatives 13, 14a, 14b, 16, and 20 were radiolabeled with carbon-11 and their log P(7.4) was calculated as a measure of their potential brain penetrance as positron emission tomography SERT imaging agents [31].
  • Neurotoxic reduction in 5-HTT protein expression seems to be limited to homozygous carriers of a long, more transcriptionally active allele of a promoter repeat polymorphism of the 5-HTT gene (SCL6A4) [32].

Physical interactions of SLC6A4

  • With the exception of the hypoglossal nucleus, where 5-HT1A receptor binding increases while SERT binding remains stable, the medullary 5-HT markers analyzed in the study are essentially "in place" at birth [33].
  • We also examine whether ITGB3 might interact with SLC6A4 to contribute to autism susceptibility [34].
  • Using a yeast one-hybrid screen, we found the transcription factor Y box binding protein 1 (YB-1) interacts with the 5-HTT VNTR [35].
  • The present data show that the SNARE protein syntaxin 1A binds the N-terminal tail of SERT, and this interaction regulates two SERT-conducting states [36].
  • In addition, SERT was found to form a complex with SCAMP2 as demonstrated by co-immunoprecipitation from a heterologous expression system and from rat brain homogenate [37].

Regulatory relationships of SLC6A4


Other interactions of SLC6A4


Analytical, diagnostic and therapeutic context of SLC6A4

  • CONCLUSIONS: This study suggested that a particular SLC6A4 haplotype harboring functional sequence variant could play a significant role in BPD etiology in Taiwan. However, due to its modest sample size, the conclusion is not final and should be confirmed in the future studies [9].
  • Linkage mapping of serotonin transporter protein gene SLC6A4 on chromosome 17 [45].
  • A cDNA encoding a serotonin transporter (5-HTT) in the human dorsal raphe nucleus was isolated and sequenced using cross-species amplification of human 5-HTT partial cDNA by the polymerase chain reaction (PCR) and the RACE-PCR procedure, designed for rapid amplification of 3' and 5' cDNA ends [46].
  • Biological assays revealed that some compounds having the N-3 atom substituted with aryl groups possess significant affinity and selectivity for monoamine transporters, and in particular, compound 5d displayed an IC50 of 21 nM toward DAT, and a good selectivity toward SERT (IC50=1042 nM) [47].
  • The L-allelic variant of the 5-HTT gene promoter, which is associated with 5-HTT overexpression, was present homozygously in 14 of 25 (56%) lung transplantation patients with SPH but in only 27% of controls [48].


  1. Association of distinct alpha(2) adrenoceptor and serotonin transporter polymorphisms with constipation and somatic symptoms in functional gastrointestinal disorders. Kim, H.J., Camilleri, M., Carlson, P.J., Cremonini, F., Ferber, I., Stephens, D., McKinzie, S., Zinsmeister, A.R., Urrutia, R. Gut (2004) [Pubmed]
  2. Mental and physical distress is modulated by a polymorphism in the 5-HT transporter gene interacting with social stressors and chronic disease burden. Grabe, H.J., Lange, M., Wolff, B., Völzke, H., Lucht, M., Freyberger, H.J., John, U., Cascorbi, I. Mol. Psychiatry (2005) [Pubmed]
  3. Receptor and transporter imaging studies in schizophrenia, depression, bulimia and Tourette's disorder--implications for psychopharmacology. Kasper, S., Tauscher, J., Willeit, M., Stamenkovic, M., Neumeister, A., Küfferle, B., Barnas, C., Stastny, J., Praschak-Rieder, N., Pezawas, L., de Zwaan, M., Quiner, S., Pirker, W., Asenbaum, S., Podreka, I., Brücke, T. World J. Biol. Psychiatry (2002) [Pubmed]
  4. MDMA (Ecstasy) and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment. Verrico, C.D., Miller, G.M., Madras, B.K. Psychopharmacology (Berl.) (2007) [Pubmed]
  5. Allelic variation in the serotonin transporter (5HTT) gene contributes to idiopathic pulmonary hypertension in children. Vachharajani, A., Saunders, S. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  6. Family-based association test of the 5HTTLPR and aggressive behavior in a general population sample of children. Haberstick, B.C., Smolen, A., Hewitt, J.K. Biol. Psychiatry. (2006) [Pubmed]
  7. Functional polymorphism within the promotor of the serotonin transporter gene is associated with severe hyperkinetic disorders. Seeger, G., Schloss, P., Schmidt, M.H. Mol. Psychiatry. (2001) [Pubmed]
  8. Transmission disequilibrium mapping at the serotonin transporter gene (SLC6A4) region in autistic disorder. Kim, S.J., Cox, N., Courchesne, R., Lord, C., Corsello, C., Akshoomoff, N., Guter, S., Leventhal, B.L., Courchesne, E., Cook, E.H. Mol. Psychiatry (2002) [Pubmed]
  9. Sequence variants and haplotype analysis of serotonin transporter gene and association with bipolar affective disorder in Taiwan. Sun, H.S., Wang, H.C., Lai, T.J., Wang, T.J., Li, C.M. Pharmacogenetics (2004) [Pubmed]
  10. Investigation of epistasis between the serotonin transporter and norepinephrine transporter genes in anorexia nervosa. Urwin, R.E., Bennetts, B.H., Wilcken, B., Beumont, P.J., Russell, J.D., Nunn, K.P. Neuropsychopharmacology (2003) [Pubmed]
  11. Meta-analysis in Psychiatric Genetics. Levinson, D.F. Current psychiatry reports. (2005) [Pubmed]
  12. Monoamine metabolites level in CSF is related to the 5-HTT gene polymorphism in treatment-resistant depression. Kishida, I., Aklillu, E., Kawanishi, C., Bertilsson, L., Agren, H. Neuropsychopharmacology (2007) [Pubmed]
  13. Screening a large reference sample to identify very low frequency sequence variants: comparisons between two genes. Glatt, C.E., DeYoung, J.A., Delgado, S., Service, S.K., Giacomini, K.M., Edwards, R.H., Risch, N., Freimer, N.B. Nat. Genet. (2001) [Pubmed]
  14. Phosphorylation and sequestration of serotonin transporters differentially modulated by psychostimulants. Ramamoorthy, S., Blakely, R.D. Science (1999) [Pubmed]
  15. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Lesch, K.P., Bengel, D., Heils, A., Sabol, S.Z., Greenberg, B.D., Petri, S., Benjamin, J., Müller, C.R., Hamer, D.H., Murphy, D.L. Science (1996) [Pubmed]
  16. Sustained release of alcohol: subcutaneous silastic implants in mice. Erickson, C.K., Koch, K.I., Mehta, C.S., McGinity, J.W. Science (1978) [Pubmed]
  17. Monoamine transporters: from genes to behavior. Gainetdinov, R.R., Caron, M.G. Annu. Rev. Pharmacol. Toxicol. (2003) [Pubmed]
  18. SERT and DAT availabilities under citalopram treatment in obsessive-compulsive disorder (OCD). Pogarell, O., Poepperl, G., Mulert, C., Hamann, C., Sadowsky, N., Riedel, M., Moeller, H.J., Hegerl, U., Tatsch, K. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. (2005) [Pubmed]
  19. Serotonin transporter inhibitors protect against hypoxic pulmonary hypertension. Marcos, E., Adnot, S., Pham, M.H., Nosjean, A., Raffestin, B., Hamon, M., Eddahibi, S. Am. J. Respir. Crit. Care Med. (2003) [Pubmed]
  20. Frontal and limbic metabolic differences in subjects selected according to genetic variation of the SLC6A4 gene polymorphism. Graff-Guerrero, A., De la Fuente-Sandoval, C., Camarena, B., Gómez-Martin, D., Apiquián, R., Fresán, A., Aguilar, A., Méndez-Núñez, J.C., Escalona-Huerta, C., Drucker-Colín, R., Nicolini, H. Neuroimage (2005) [Pubmed]
  21. Prediction of dopamine transporter binding availability by genotype: a preliminary report. Jacobsen, L.K., Staley, J.K., Zoghbi, S.S., Seibyl, J.P., Kosten, T.R., Innis, R.B., Gelernter, J. The American journal of psychiatry. (2000) [Pubmed]
  22. Meta-analysis reveals association between serotonin transporter gene STin2 VNTR polymorphism and schizophrenia. Fan, J.B., Sklar, P. Mol. Psychiatry (2005) [Pubmed]
  23. Influence of serotonin transporter gene polymorphisms on cognitive decline and cognitive abilities in a nondemented elderly population. Payton, A., Gibbons, L., Davidson, Y., Ollier, W., Rabbitt, P., Worthington, J., Pickles, A., Pendleton, N., Horan, M. Mol. Psychiatry (2005) [Pubmed]
  24. Serotonin transporter genetic variation and the response of the human amygdala. Hariri, A.R., Mattay, V.S., Tessitore, A., Kolachana, B., Fera, F., Goldman, D., Egan, M.F., Weinberger, D.R. Science (2002) [Pubmed]
  25. Serotonin transporter gene polymorphism and myocardial infarction: Etude Cas-Témoins de l'Infarctus du Myocarde (ECTIM). Fumeron, F., Betoulle, D., Nicaud, V., Evans, A., Kee, F., Ruidavets, J.B., Arveiler, D., Luc, G., Cambien, F. Circulation (2002) [Pubmed]
  26. Localization and dynamic regulation of biogenic amine transporters in the mammalian central nervous system. Hoffman, B.J., Hansson, S.R., Mezey, E., Palkovits, M. Frontiers in neuroendocrinology. (1998) [Pubmed]
  27. Human serotonin transporter variants display altered sensitivity to protein kinase G and p38 mitogen-activated protein kinase. Prasad, H.C., Zhu, C.B., McCauley, J.L., Samuvel, D.J., Ramamoorthy, S., Shelton, R.C., Hewlett, W.A., Sutcliffe, J.S., Blakely, R.D. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  28. Investigation of serotonin-related genes in antidepressant response. Peters, E.J., Slager, S.L., McGrath, P.J., Knowles, J.A., Hamilton, S.P. Mol. Psychiatry (2004) [Pubmed]
  29. Evidence for a combined genetic effect of the 5-HT(1A) receptor and serotonin transporter genes in the clinical outcome of major depressive patients treated with citalopram. Arias, B., Catalán, R., Gastó, C., Gutiérrez, B., Fañanás, L. J. Psychopharmacol. (Oxford) (2005) [Pubmed]
  30. Family-based association study of the serotonin transporter gene polymorphisms in Korean ADHD trios. Kim, S.J., Badner, J., Cheon, K.A., Kim, B.N., Yoo, H.J., Kim, S.J., Cook, E., Leventhal, B.L., Kim, Y.S. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2005) [Pubmed]
  31. Synthesis, in vitro characterization, and radiolabeling of N,N-dimethyl-2-(2'-amino-4'-substituted-phenylthio)benzylamines: potential candidates as selective serotonin transporter radioligands. Jarkas, N., McConathy, J., Voll, R.J., Goodman, M.M. J. Med. Chem. (2005) [Pubmed]
  32. Genotype effects on neurodegeneration and neuroadaptation in monoaminergic neurotransmitter systems. Heinz, A., Goldman, D. Neurochem. Int. (2000) [Pubmed]
  33. Differential development of 5-HT receptor and the serotonin transporter binding in the human infant medulla. Paterson, D.S., Belliveau, R.A., Trachtenberg, F., Kinney, H.C. J. Comp. Neurol. (2004) [Pubmed]
  34. ITGB3 shows genetic and expression interaction with SLC6A4. Weiss, L.A., Ober, C., Cook, E.H. Hum. Genet. (2006) [Pubmed]
  35. YB-1 and CTCF differentially regulate the 5-HTT polymorphic intron 2 enhancer which predisposes to a variety of neurological disorders. Klenova, E., Scott, A.C., Roberts, J., Shamsuddin, S., Lovejoy, E.A., Bergmann, S., Bubb, V.J., Royer, H.D., Quinn, J.P. J. Neurosci. (2004) [Pubmed]
  36. Regulating the conducting states of a mammalian serotonin transporter. Quick, M.W. Neuron (2003) [Pubmed]
  37. Subcellular redistribution of the serotonin transporter by secretory carrier membrane protein 2. Müller, H.K., Wiborg, O., Haase, J. J. Biol. Chem. (2006) [Pubmed]
  38. Pharmacological characterization of ecstasy synthesis byproducts with recombinant human monoamine transporters. Pifl, C., Nagy, G., Berényi, S., Kattinger, A., Reither, H., Antus, S. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  39. A new positron emission tomography imaging agent for the serotonin transporter: synthesis, pharmacological characterization, and kinetic analysis of [11C]2-[2-(dimethylaminomethyl)phenylthio]-5-fluoromethylphenylamine ([11C]AFM). Huang, Y., Hwang, D.R., Bae, S.A., Sudo, Y., Guo, N., Zhu, Z., Narendran, R., Laruelle, M. Nucl. Med. Biol. (2004) [Pubmed]
  40. Estrogen receptor beta (ERbeta) mRNA and protein in serotonin neurons of macaques. Gundlah, C., Lu, N.Z., Mirkes, S.J., Bethea, C.L. Brain Res. Mol. Brain Res. (2001) [Pubmed]
  41. Serotonin transporter (5-HTT) promoter genotype may influence the prolactin response to clomipramine. Whale, R., Quested, D.J., Laver, D., Harrison, P.J., Cowen, P.J. Psychopharmacology (Berl.) (2000) [Pubmed]
  42. Genetic association analysis of serotonin system genes in bipolar affective disorder. Vincent, J.B., Masellis, M., Lawrence, J., Choi, V., Gurling, H.M., Parikh, S.V., Kennedy, J.L. The American journal of psychiatry. (1999) [Pubmed]
  43. Catechol o-methyltransferase, serotonin transporter, and tryptophan hydroxylase gene polymorphisms in bipolar disorder patients with and without comorbid panic disorder. Rotondo, A., Mazzanti, C., Dell'Osso, L., Rucci, P., Sullivan, P., Bouanani, S., Gonnelli, C., Goldman, D., Cassano, G.B. The American journal of psychiatry. (2002) [Pubmed]
  44. Genetic polymorphisms and personality in healthy adults: a systematic review and meta-analysis. Munafò, M.R., Clark, T.G., Moore, L.R., Payne, E., Walton, R., Flint, J. Mol. Psychiatry (2003) [Pubmed]
  45. Linkage mapping of serotonin transporter protein gene SLC6A4 on chromosome 17. Gelernter, J., Pakstis, A.J., Kidd, K.K. Hum. Genet. (1995) [Pubmed]
  46. Isolation of a cDNA encoding the human brain serotonin transporter. Lesch, K.P., Wolozin, B.L., Estler, H.C., Murphy, D.L., Riederer, P. J. Neural Transm. Gen. Sect. (1993) [Pubmed]
  47. 3-Aza-6,8-dioxabicyclo[3.2.1]octanes as new enantiopure heteroatom-rich tropane-like ligands of human dopamine transporter. Cini, N., Danieli, E., Menchi, G., Trabocchi, A., Bottoncetti, A., Raspanti, S., Pupi, A., Guarna, A. Bioorg. Med. Chem. (2006) [Pubmed]
  48. Serotonin-induced smooth muscle hyperplasia in various forms of human pulmonary hypertension. Marcos, E., Fadel, E., Sanchez, O., Humbert, M., Dartevelle, P., Simonneau, G., Hamon, M., Adnot, S., Eddahibi, S. Circ. Res. (2004) [Pubmed]
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