Disease relevance of SLC6A11

• The gamma amino butyric acid (GABA) transporters GAT-1 and GAT-3 were localized by immunohistochemistry in hippocampi removed for the control of medically intractable temporal lobe epilepsy (TLE) [1].
• Further study is necessary to elucidate GAT-3 expression in neurological conditions, including hyperalgesia and Parkinson's disease [2].

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

• We expressed the mouse gamma-aminobutyric acid (GABA) transporter GAT4 (homologous to rat/ human GAT-3) in Xenopus laevis oocytes and examined its functional and pharmacological properties by using electrophysiological and tracer uptake methods [9].
• Due to its lipophilicity, (S)-SNAP-5114 is also expected to cross the blood-brain-barrier and therefore, should be an important tool for evaluating the role of GAT-3 in neural function [10].
• Furthermore, reverse transcription-PCR and Western blot analyses revealed that GAT2 and GAT3 are expressed in primary cultures of astrocytes [6].
• TsTX-V did not reduce (3)H-GABA uptake in COS-7 cells expressing the GABA transporters GAT-1 and GAT-3, suggesting that this toxin indirectly reduces the transport [11].
• Immunoreactivity for multiple GABA transporters (GAT-1, GAT-2, GAT-3) in the gerbil pineal gland [12].

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

• Electron microscopy showed that GAT-3 immunoreactivity was present in cell bodies with light cytoplasm and dense bundles of glial filaments, and features of astrocytes [2].

References