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SLC6A11  -  solute carrier family 6 (neurotransmitter...

Homo sapiens

Synonyms: GABT3, GAT-3, GAT3, GAT4, Sodium-and chloride-dependent GABA transporter 3, ...
 
 
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Disease relevance of SLC6A11

 

High impact information on SLC6A11

  • cDNA clones encoding two novel gamma-aminobutyric acid (GABA) transporters (designated GAT-2 and GAT-3) have been isolated from rat brain, and their functional properties have been examined in mammalian cells [3].
  • RESULTS: Compared with autopsies, non-HS cases with similar neuron counts showed: 1) increased GAD IR gray values (GV) in the fascia dentata outer molecular layer (OML), hilus, and stratum radiatum; 2) increased GAT-1 OML GVs; 3) increased astrocytic GAT-3 GVs in the hilus and Ammon's horn; and 4) no IR differences for EAAT3-1 [4].
  • These effects are selective; protein levels of the astrocyte GABA transporter GAT-3 were unaffected in the medial thalamus [5].
  • In addition, Zn(2+), which has been reported to be a potent inhibitor of GAT3, was found to have a significantly but partially inhibitory effect on the Na(+)-dependent GABA transport in a concentration-dependent manner [6].
  • GAT1 and GAT3 expression are differently localized in the human epileptogenic hippocampus [1].
 

Biological context of SLC6A11

  • A human liver cDNA library was initially screened by a 32P-labeled murine brain GABA transporter 3 (GAT-3) cDNA probe, and full-length cDNA was cloned by employing Marathon-Ready human kidney cDNA [7].
  • The nucleotide sequences of GAT-2 and GAT-3 predict proteins of 602 and 627 amino acids, respectively, which can be modeled with 12 transmembrane domains, similar to the topology proposed for other cloned neurotransmitter transporters [3].
  • We suggest that differences in GAT distribution, especially the expression of GAT-3 by oligodendrocytes in humans, must be accommodated in extrapolating rodent models of GABA homeostasis to humans [8].
 

Anatomical context of SLC6A11

 

Associations of SLC6A11 with chemical compounds

  • Design, synthesis and evaluation of substituted triarylnipecotic acid derivatives as GABA uptake inhibitors: identification of a ligand with moderate affinity and selectivity for the cloned human GABA transporter GAT-3 [13].
  • Search of published sequences revealed high homology with rat GAT-2, murine GAT-3 cDNA, human solute carrier family 6 member 13 (SLC6A13), and a human peripheral betaine/GABA transporter [7].
  • New highly potent GABA uptake inhibitors selective for GAT-1 and GAT-3 derived from (R)- and (S)-proline and homologous pyrrolidine-2-alkanoic acids [14].
  • Using post mortem tissue from individuals diagnosed with schizophrenia (n=6) and control subjects (n=6), the density of GAT-1 was established by displacing [3H]GABA with muscimol, and for GAT-3 [3H]beta-alanine was used [15].
 

Other interactions of SLC6A11

  • For the GAT-2, GAT-3 and BGT-1 subtypes only compounds with a small preference for one of the subtypes have been published [16].
  • When these experiments were repeated in hippocampal slices, similar results were obtained except that a GAT1- and GAT3-independent nonvesicular source(s) of GABA was found to contribute to the tonic current [17].
 

Analytical, diagnostic and therapeutic context of SLC6A11

References

  1. GAT1 and GAT3 expression are differently localized in the human epileptogenic hippocampus. Lee, T.S., Bjørnsen, L.P., Paz, C., Kim, J.H., Spencer, S.S., Spencer, D.D., Eid, T., de Lanerolle, N.C. Acta Neuropathol. (2006) [Pubmed]
  2. A light and electron microscopic study of the GABA transporter GAT-3 in the monkey basal ganglia and brainstem. Ng, C.H., Wang, X.S., Ong, W.Y. J. Neurocytol. (2000) [Pubmed]
  3. Molecular heterogeneity of the gamma-aminobutyric acid (GABA) transport system. Cloning of two novel high affinity GABA transporters from rat brain. Borden, L.A., Smith, K.E., Hartig, P.R., Branchek, T.A., Weinshank, R.L. J. Biol. Chem. (1992) [Pubmed]
  4. Hippocampal GABA and glutamate transporter immunoreactivity in patients with temporal lobe epilepsy. Mathern, G.W., Mendoza, D., Lozada, A., Pretorius, J.K., Dehnes, Y., Danbolt, N.C., Nelson, N., Leite, J.P., Chimelli, L., Born, D.E., Sakamoto, A.C., Assirati, J.A., Fried, I., Peacock, W.J., Ojemann, G.A., Adelson, P.D. Neurology (1999) [Pubmed]
  5. Selective down-regulation of the astrocyte glutamate transporters GLT-1 and GLAST within the medial thalamus in experimental Wernicke's encephalopathy. Hazell, A.S., Rao, K.V., Danbolt, N.C., Pow, D.V., Butterworth, R.F. J. Neurochem. (2001) [Pubmed]
  6. Functional characterization of Zn2(+)-sensitive GABA transporter expressed in primary cultures of astrocytes from rat cerebral cortex. Wu, Q., Wada, M., Shimada, A., Yamamoto, A., Fujita, T. Brain Res. (2006) [Pubmed]
  7. Sequence and chromosomal assignment of a human novel cDNA: similarity to gamma-aminobutyric acid transporter. Gong, Y., Zhang, M., Cui, L., Minuk, G.Y. Can. J. Physiol. Pharmacol. (2001) [Pubmed]
  8. Differential expression of the GABA transporters GAT-1 and GAT-3 in brains of rats, cats, monkeys and humans. Pow, D.V., Sullivan, R.K., Williams, S.M., Scott, H.L., Dodd, P.R., Finkelstein, D. Cell Tissue Res. (2005) [Pubmed]
  9. Novel properties of a mouse gamma-aminobutyric acid transporter (GAT4). Karakossian, M.H., Spencer, S.R., Gomez, A.Q., Padilla, O.R., Sacher, A., Loo, D.D., Nelson, N., Eskandari, S. J. Membr. Biol. (2005) [Pubmed]
  10. Cloning of the human homologue of the GABA transporter GAT-3 and identification of a novel inhibitor with selectivity for this site. Borden, L.A., Dhar, T.G., Smith, K.E., Branchek, T.A., Gluchowski, C., Weinshank, R.L. Recept. Channels (1994) [Pubmed]
  11. Effects of Tityus serrulatus scorpion venom and its toxin TsTX-V on neurotransmitter uptake in vitro. Cecchini, A.L., Vasconcelos, F., Amara, S.G., Giglio, J.R., Arantes, E.C. Toxicol. Appl. Pharmacol. (2006) [Pubmed]
  12. Immunoreactivity for multiple GABA transporters (GAT-1, GAT-2, GAT-3) in the gerbil pineal gland. Redecker, P. Neurosci. Lett. (1999) [Pubmed]
  13. Design, synthesis and evaluation of substituted triarylnipecotic acid derivatives as GABA uptake inhibitors: identification of a ligand with moderate affinity and selectivity for the cloned human GABA transporter GAT-3. Dhar, T.G., Borden, L.A., Tyagarajan, S., Smith, K.E., Branchek, T.A., Weinshank, R.L., Gluchowski, C. J. Med. Chem. (1994) [Pubmed]
  14. New highly potent GABA uptake inhibitors selective for GAT-1 and GAT-3 derived from (R)- and (S)-proline and homologous pyrrolidine-2-alkanoic acids. Fülep, G.H., Hoesl, C.E., Höfner, G., Wanner, K.T. European journal of medicinal chemistry. (2006) [Pubmed]
  15. GABA transporters GAT-1 and GAT-3 in the human dorsolateral prefrontal cortex in schizophrenia. Schleimer, S.B., Hinton, T., Dixon, G., Johnston, G.A. Neuropsychobiology (2004) [Pubmed]
  16. The GABA transporter and its inhibitors. Soudijn, W., van Wijngaarden, I. Current medicinal chemistry. (2000) [Pubmed]
  17. The Transmembrane Sodium Gradient Influences Ambient GABA Concentration by Altering the Equilibrium of GABA Transporters. Wu, Y., Wang, W., Richerson, G.B. J. Neurophysiol. (2006) [Pubmed]
 
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