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Gene Review

Slc6a4  -  solute carrier family 6 (neurotransmitter...

Mus musculus

Synonyms: 5-HTT, 5HT transporter, 5HTT, AI323329, Htt, ...
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Disease relevance of Slc6a4

  • These results demonstrate that osteoblastic cells express a functional serotonin system, with mechanisms for responding to and regulating uptake of 5-HT, and disruption of the 5-HTT gene may cause osteopenia [1].
  • Previous studies demonstrated that the serotonin (5-hydroxytryptamine; 5-HT) transporter (5-HTT) mediates the mitogenic activity of 5-HT in pulmonary vascular SMCs and is overexpressed during hypoxia [2].
  • On a preliminary screen for gross physical, neurological and behavioral functions, all measures were normal with the exception that 5-HTT -/- mice on the C57BL/6J background showed increased body weight and poor rotarod performance, and 5-HTT -/- mice on the 129S6 background showed reduced neuromuscular strength [3].
  • Initial studies evaluated the dose-response and time course of 8-OH-DPAT-induced hypothermia and hormone secretion in normal CD-1 mice (the background strain of the 5-HTT knockout mice) [4].
  • 5-HTT-/- mice did not develop thermal hyperalgesia, but showed bilateral mechanical allodynia after the nerve injury [5].

Psychiatry related information on Slc6a4


High impact information on Slc6a4

  • This occurred despite potentiation of acute hypoxic pulmonary vasoconstriction in the 5-HTT(-/-) mice [2].
  • These data further support a key role of 5-HTT in hypoxia-induced pulmonary vascular SMC proliferation and pulmonary hypertension [2].
  • These results indicate that functional deficits in this pathway in 5-HTT(-/-) mice may be due to excessive postnatal 5-HT activity [10].
  • With or without postnatal p-chlorophenylalanine treatment, 5-HTT(-/-) mice exhibited lower resting (unstimulated) lCMR(glc) than did 5-HTT(+/+) controls in the whisker-to-barrel cortex pathway and throughout the brain [10].
  • FGF-2 was neuroprotective as well, because it blocked cell death induced by mutant expanded Htt in primary striatal cultures [11].

Chemical compound and disease context of Slc6a4


Biological context of Slc6a4

  • A relatively high density of nanomolar affinity 5-HTT binding sites is present in ROS 17/2.8 and UMR 106-H5 cells [1].
  • Since serotonin (5-HT) plays a role as a regulator of craniofacial morphogenesis, we explored the expression and function of 5-HT receptors and the 5-HT transporter (5-HTT) in bone [1].
  • 5. Our data suggest that these polymorphic variable number of tandem repeats regions act as transcriptional regulators and have allele-dependent differential enhancer-like properties within an area of the hindbrain where the 5-HTT gene is known to be transcribed at this stage of development [6].
  • Together, these data suggest that the presence of a functional 5-HTT is essential for brain 5-HT homeostasis and for 3,4-methylenedioxymethamphetamine-induced hyperactivity [12].
  • Despite evidence that excess extracellular 5-HT during embryonic development, including that produced by drugs that inhibit the 5-HTT, may lead to severe craniofacial and cardiac malformations, no obvious developmental phenotype was observed in the 5-HTT-/- mice [12].

Anatomical context of Slc6a4

  • The repeated administration of MDMA (10 mg/kg x 3, 3-h intervals, s.c.) significantly decreased the contents of 5-HT and its major metabolite 5-hydroxyindole acetic acid (5-HIAA) in the frontal cortex and hippocampus, and the density of the 5-HT transporter (5-HTT) in the frontal cortex, hippocampus and striatum [13].
  • Primary cultures of rat osteoblasts (rOB) and a variety of clonal osteoblastic cell lines including ROS 17/2.8, UMR 106-H5 and Py1a show mRNA expression for the 5-HTT, and the 5-HT(1A), 5-HT(1D), 5-HT(2A) and 5-HT(2B) receptors by RT-PCR analysis and immunoblot [1].
  • In 5-HTT (-/-) animals, cancellous bone volume (BV/TV) in the lumbar vertebrae is reduced, with a trend toward decreased trabecular thickness and trabecular number [1].
  • These results indicate a role for 5-HTT in osteoclast function and suggest that commonly used antidepressive agents may affect bone mass [14].
  • The functional properties of GABA(B) receptors were examined in the dorsal raphe nucleus (DRN) and the hippocampus of knock-out mice devoid of the 5-HT transporter (5-HTT-/-) or the 5-HT(1A) receptor (5-HT(1A)-/-) [15].

Associations of Slc6a4 with chemical compounds


Physical interactions of Slc6a4


Regulatory relationships of Slc6a4


Other interactions of Slc6a4


Analytical, diagnostic and therapeutic context of Slc6a4


  1. The role of dopamine and serotonin in regulating bone mass and strength: studies on dopamine and serotonin transporter null mice. Bliziotes, M., Gunness, M., Eshleman, A., Wiren, K. Journal of musculoskeletal & neuronal interactions. (2002) [Pubmed]
  2. Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene. Eddahibi, S., Hanoun, N., Lanfumey, L., Lesch, K.P., Raffestin, B., Hamon, M., Adnot, S. J. Clin. Invest. (2000) [Pubmed]
  3. Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter. Holmes, A., Yang, R.J., Murphy, D.L., Crawley, J.N. Neuropsychopharmacology (2002) [Pubmed]
  4. Reduction of 5-hydroxytryptamine (5-HT)(1A)-mediated temperature and neuroendocrine responses and 5-HT(1A) binding sites in 5-HT transporter knockout mice. Li, Q., Wichems, C., Heils, A., Van De Kar, L.D., Lesch, K.P., Murphy, D.L. J. Pharmacol. Exp. Ther. (1999) [Pubmed]
  5. Absence of thermal hyperalgesia in serotonin transporter-deficient mice. Vogel, C., Mössner, R., Gerlach, M., Heinemann, T., Murphy, D.L., Riederer, P., Lesch, K.P., Sommer, C. J. Neurosci. (2003) [Pubmed]
  6. A serotonin transporter gene intron 2 polymorphic region, correlated with affective disorders, has allele-dependent differential enhancer-like properties in the mouse embryo. MacKenzie, A., Quinn, J. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  7. Synthesis, monoamine transporter binding properties, and behavioral pharmacology of a series of 3beta-(substituted phenyl)-2beta-(3'-substituted isoxazol-5-yl)tropanes. Carroll, F.I., Pawlush, N., Kuhar, M.J., Pollard, G.T., Howard, J.L. J. Med. Chem. (2004) [Pubmed]
  8. Differential expression of monoamine oxidase A, serotonin transporter, tyrosine hydroxylase and norepinephrine transporter mRNA by anorexia mutation and food deprivation. Jahng, J.W., Houpt, T.A., Joh, T.H., Son, J.H. Brain Res. Dev. Brain Res. (1998) [Pubmed]
  9. Mice lacking the serotonin transporter exhibit 5-HT(1A) receptor-mediated abnormalities in tests for anxiety-like behavior. Holmes, A., Yang, R.J., Lesch, K.P., Crawley, J.N., Murphy, D.L. Neuropsychopharmacology (2003) [Pubmed]
  10. Developmental disruption of serotonin transporter function impairs cerebral responses to whisker stimulation in mice. Esaki, T., Cook, M., Shimoji, K., Murphy, D.L., Sokoloff, L., Holmes, A. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  11. FGF-2 promotes neurogenesis and neuroprotection and prolongs survival in a transgenic mouse model of Huntington's disease. Jin, K., LaFevre-Bernt, M., Sun, Y., Chen, S., Gafni, J., Crippen, D., Logvinova, A., Ross, C.A., Greenberg, D.A., Ellerby, L.M. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  12. Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4-methylenedioxymethamphetamine ("Ecstasy") in serotonin transporter-deficient mice. Bengel, D., Murphy, D.L., Andrews, A.M., Wichems, C.H., Feltner, D., Heils, A., Mössner, R., Westphal, H., Lesch, K.P. Mol. Pharmacol. (1998) [Pubmed]
  13. Protective effects of minocycline on 3,4-methylenedioxymethamphetamine-induced neurotoxicity in serotonergic and dopaminergic neurons of mouse brain. Zhang, L., Shirayama, Y., Shimizu, E., Iyo, M., Hashimoto, K. Eur. J. Pharmacol. (2006) [Pubmed]
  14. Serotonin regulates osteoclast differentiation through its transporter. Battaglino, R., Fu, J., Späte, U., Ersoy, U., Joe, M., Sedaghat, L., Stashenko, P. J. Bone Miner. Res. (2004) [Pubmed]
  15. GABA(B) receptors in 5-HT transporter- and 5-HT1A receptor-knock-out mice: further evidence of a transduction pathway shared with 5-HT1A receptors. Mannoury la Cour, C., Hanoun, N., Melfort, M., Hen, R., Lesch, K.P., Hamon, M., Lanfumey, L. J. Neurochem. (2004) [Pubmed]
  16. Aberrant accumulation of serotonin in dopaminergic neurons. Mössner, R., Simantov, R., Marx, A., Lesch, K.P., Seif, I. Neurosci. Lett. (2006) [Pubmed]
  17. Cocaine reward models: conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice. Sora, I., Wichems, C., Takahashi, N., Li, X.F., Zeng, Z., Revay, R., Lesch, K.P., Murphy, D.L., Uhl, G.R. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  18. Brain region-specific alterations of 5-HT2A and 5-HT2C receptors in serotonin transporter knockout mice. Li, Q., Wichems, C.H., Ma, L., Van de Kar, L.D., Garcia, F., Murphy, D.L. J. Neurochem. (2003) [Pubmed]
  19. Regional changes in density of serotonin transporter in the brain of 5-HT1A and 5-HT1B knockout mice, and of serotonin innervation in the 5-HT1B knockout. Ase, A.R., Reader, T.A., Hen, R., Riad, M., Descarries, L. J. Neurochem. (2001) [Pubmed]
  20. Gender-dependent regulation of G-protein-gated inwardly rectifying potassium current in dorsal raphe neurons in knock-out mice devoid of the 5-hydroxytryptamine transporter. Loucif, A.J., Bonnavion, P., Macri, B., Golmard, J.L., Boni, C., Melfort, M., Leonard, G., Lesch, K.P., Adrien, J., Jacquin, T.D. J. Neurobiol. (2006) [Pubmed]
  21. mPet-1, a mouse ETS-domain transcription factor, is expressed in central serotonergic neurons. Pfaar, H., von Holst, A., Vogt Weisenhorn, D.M., Brodski, C., Guimera, J., Wurst, W. Dev. Genes Evol. (2002) [Pubmed]
  22. Altered expression and functions of serotonin 5-HT1A and 5-HT1B receptors in knock-out mice lacking the 5-HT transporter. Fabre, V., Beaufour, C., Evrard, A., Rioux, A., Hanoun, N., Lesch, K.P., Murphy, D.L., Lanfumey, L., Hamon, M., Martres, M.P. Eur. J. Neurosci. (2000) [Pubmed]
  23. Alcohol intake after serotonin transporter inactivation in mice. Kelaï, S., Aïssi, F., Lesch, K.P., Cohen-Salmon, C., Hamon, M., Lanfumey, L. Alcohol Alcohol. (2003) [Pubmed]
  24. Exaggerated adrenomedullary response to immobilization in mice with targeted disruption of the serotonin transporter gene. Tjurmina, O.A., Armando, I., Saavedra, J.M., Goldstein, D.S., Murphy, D.L. Endocrinology (2002) [Pubmed]
  25. Abnormal trafficking and subcellular localization of an N-terminally truncated serotonin transporter protein. Ravary, A., Muzerelle, A., Darmon, M., Murphy, D.L., Moessner, R., Lesch, K.P., Gaspar, P. Eur. J. Neurosci. (2001) [Pubmed]
  26. Organic cation transporter capable of transporting serotonin is up-regulated in serotonin transporter-deficient mice. Schmitt, A., Mössner, R., Gossmann, A., Fischer, I.G., Gorboulev, V., Murphy, D.L., Koepsell, H., Lesch, K.P. J. Neurosci. Res. (2003) [Pubmed]
  27. Sex hormone-dependent desensitization of 5-HT1A autoreceptors in knockout mice deficient in the 5-HT transporter. Bouali, S., Evrard, A., Chastanet, M., Lesch, K.P., Hamon, M., Adrien, J. Eur. J. Neurosci. (2003) [Pubmed]
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