Alternative titles; symbols
HGNC Approved Gene Symbol: SLC6A11
Cytogenetic location: 3p25.3 Genomic coordinates (GRCh38): 3:10,816,228-10,940,714 (from NCBI)
Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter. GABAergic neurotransmission is terminated by the uptake of GABA into the presynaptic terminal and the surrounding astroglial cells by sodium-dependent transporters, such as SLC6A11 (Borden et al., 1994).
By screening a human fetal brain cDNA library with rat Gat3, Borden et al. (1994) cloned SLC6A11, which they designated GAT3. The deduced 632-amino acid protein contains 12 transmembrane domains and several putative N-glycosylation sites. GAT3 shares 95% identity with rat Gat3. Northern blot analysis of total human brain RNA detected a single GAT3 transcript of about 3.8 kb.
Borden et al. (1994) confirmed specific uptake of radiolabeled GABA by GAT3 following transfection into mouse fibroblasts and COS-7 cells.
Physiologic concentrations of zinc have anticonvulsive effects and are neuroprotective. Using tracer flux and electrophysiologic methods with Xenopus oocytes expressing mouse GATA transporters, Cohen-Kfir et al. (2005) showed that zinc potently inhibited GABA uptake mediated by Gat4. Zinc also inhibited Gat2 (SLC6A12; 603080), but it only weakly inhibited Gat3 (SLC6A13; 615097) and had no effect on Gat1 (SLC6A1; 137165). Closer examination of zinc inhibition of Gat4 revealed high-affinity and low-affinity interaction sites, and the inhibitory effect of zinc was enhanced by Na+ in a concentration-dependent manner. Use of a Gat3/Gat4 chimeric transporter revealed that zinc interacted with Gat4 at 2 sites in its C-terminal half. Zinc also inhibited GABA-evoked steady-state inward current and voltage-induced presteady-state charge movement by Gat4 and the Gat3/Gat4 chimeric transporter, but it did not alter the time constants for presteady-state current relaxation. Immunohistochemical analysis of adult rat brain revealed that Gat4 was enriched in hippocampal CA1 and CA3 regions, which are heavily populated by zinc-containing glutamatergic neurons. Cohen-Kfir et al. (2005) concluded that zinc released by hyperactive glutamatergic neurons may simultaneously inhibit GABAergic neurons via GAT4 and play a neuroprotective role against glutamate-induced excitotoxicity.
Clarkson et al. (2010) showed that after a stroke in mice, tonic neuronal inhibition is increased in the peri-infarct zone. This increased tonic inhibition is mediated by extrasynaptic GABA-A receptors and is caused by an impairment in GABA transporter (Gat3/Gat4) function. To counteract the heightened inhibition, Clarkson et al. (2010) administered in vivo a benzodiazepine inverse agonist specific for alpha-5-subunit (GABRA5; 137142)-containing extrasynaptic GABA-A receptors at a delay after stroke. This treatment produced an early and sustained recovery of motor function. Genetically lowering the number of alpha-5- or delta-subunit (GABRD; 137163)-containing GABA-A receptors responsible for tonic inhibition also proved beneficial for recovery after stroke, consistent with the therapeutic potential of diminishing extrasynaptic GABA-A receptor function.
Borden, L. A., Dhar, T. G., Smith, K. E., Branchek, T. A., Gluchowski, C., Weinshank, R. L. Cloning of the human homologue of the GABA transporter GAT-3 and identification of a novel inhibitor with selectivity for this site. Receptors Channels 2: 207-213, 1994. [PubMed: 7874447]
Clarkson, A. N., Huang, B. S., MacIsaac, S. E., Mody, I., Carmichael, S. T. Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature 468: 305-309, 2010. [PubMed: 21048709] [Full Text: https://doi.org/10.1038/nature09511]
Cohen-Kfir, E., Lee, W., Eskandari, S., Nelson, N. Zinc inhibition of gamma-aminobutyric acid transporter 4 (GAT4) reveals a link between excitatory and inhibitory neurotransmission. Proc. Nat. Acad. Sci. 102: 6154-6159, 2005. [PubMed: 15829583] [Full Text: https://doi.org/10.1073/pnas.0501431102]