The activity of GABA-transporters located predominantly upon neurones (GAT-1), glia (GAT-3) or both (GAT-2, BGT-1) serves to terminate phasic GABA-ergic transmission, maintain low ambient extracellular concentrations of GABA, and recycle GABA for reuse by neurones. Nonetheless, ambient concentrations of GABA are sufficient to sustain tonic inhibition mediated by high affinity GABA_A receptors in certain neuronal populations [18]. GAT1 is the predominant GABA transporter in the brain and occurs primarily upon the terminals of presynaptic neurones and to a much lesser extent upon distal astocytic processes that are in proximity to axons terminals. GAT3 resides predominantly on distal astrocytic terminals that are close to the GABAergic synapse. By contrast, BGT1 occupies an extrasynaptic location possibly along with GAT2 which has limited expression in the brain [15]. TauT is a high affinity taurine transporter involved in osmotic balance that occurs in the brain and non-neuronal tissues, such as the kidney, brush border membrane of the intestine and blood brain barrier [4,12]. CT1, which transports creatine, has a ubiquitous expression pattern, often co-localizing with creatine kinase [4].

The IC₅₀ values for GAT1-4 reported in the table reflect the range reported in the literature from studies of both human and mouse transporters. There is a tendency towards lower IC₅₀ values for the human orthologue [14]. SNAP-5114 is only weakly selective for GAT 2 and GAT3, with IC₅₀ values in the range 22 to >30 µM at GAT1 and BGT1, whereas NNC052090 has at least an order of magnitude selectivity for BGT1 [see [5,17] for reviews]. Compound (R)-4d [PMID: 16766089] is a recently described compound that displays 20-fold selectivity for GAT3 over GAT1 [11]. In addition to the inhibitors listed, deramciclane is a moderately potent, though non-selective, inhibitor of all cloned GABA transporters (IC₅₀ = 26-46 µM; [8]). Diaryloxime and diarylvinyl ether derivatives of nipecotic acid and guvacine that potently inhibit the uptake of [³H]GABA into rat synaptosomes have been described [13]. Several derivatives of exo-THPO (e.g. N-methyl-exo-THPO and N-acetyloxyethyl-exo-THPO) demonstrate selectivity as blockers of astroglial, versus neuronal, uptake of GABA [see [5,16] for reviews]. GAT3 is inhibited by physiologically relevant concentrations of Zn²⁺ [6]. Taut transports GABA, but with low affinity, but CT1 does not, although it can be engineered to do so by mutagenesis guided by LeuT as a structural template [10]. Although inhibitors of creatine transport by CT1 (e.g. β-guanidinopropionic acid, cyclocreatine, guanidinoethane sulfonic acid) are known (e.g. [7]) they insufficiently characterized to be included in the table.

1. Anderson CM, Howard A, Walters JR, Ganapathy V, Thwaites DT. (2009) Taurine uptake across the human intestinal brush-border membrane is via two transporters: H+-coupled PAT1 (SLC36A1) and Na+- and Cl(-)-dependent TauT (SLC6A6). J Physiol (Lond.), 587 (Pt 4): 731-44. [PMID:19074966]

2. Borden LA, Dhar TG, Smith KE, Branchek TA, Gluchowski C, Weinshank RL. (1994) Cloning of the human homologue of the GABA transporter GAT-3 and identification of a novel inhibitor with selectivity for this site. Recept Channels, 2 (3): 207-13. [PMID:7874447]

3. Borden LA, Murali Dhar TG, Smith KE, Weinshank RL, Branchek TA, Gluchowski C. (1994) Tiagabine, SK&F 89976-A, CI-966, and NNC-711 are selective for the cloned GABA transporter GAT-1. Eur J Pharmacol, 269 (2): 219-24. [PMID:7851497]

4. Chen NH, Reith ME, Quick MW. (2004) Synaptic uptake and beyond: the sodium- and chloride-dependent neurotransmitter transporter family SLC6. Pflugers Arch, 447 (5): 519-31. [PMID:12719981]

5. Clausen RP, Madsen K, Larsson OM, Frølund B, Krogsgaard-Larsen P, Schousboe A. (2006) Structure-activity relationship and pharmacology of gamma-aminobutyric acid (GABA) transport inhibitors. Adv Pharmacol, 54: 265-84. [PMID:17175818]

6. Cohen-Kfir E, Lee W, Eskandari S, Nelson N. (2005) Zinc inhibition of gamma-aminobutyric acid transporter 4 (GAT4) reveals a link between excitatory and inhibitory neurotransmission. Proc Natl Acad Sci USA, 102 (17): 6154-9. [PMID:15829583]

7. Dai W, Vinnakota S, Qian X, Kunze DL, Sarkar HK. (1999) Molecular characterization of the human CRT-1 creatine transporter expressed in Xenopus oocytes. Arch Biochem Biophys, 361 (1): 75-84. [PMID:9882430]

8. Dhar TG, Borden LA, Tyagarajan S, Smith KE, Branchek TA, Weinshank RL, Gluchowski C. (1994) 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. J Med Chem, 37 (15): 2334-42. [PMID:8057281]

9. Dhar TGM, Nakanishi H, Borden LA, Gluchowski C. (1996) On the bioactive conformation of the GABA uptake inhibitor SK&F 89976-A. Bioorg Med Chem Lett, 6 (13): 1535 -1540. DOI: 10.1016/S0960-894X(96)00268-5

10. Dodd JR, Christie DL. (2007) Selective amino acid substitutions convert the creatine transporter to a gamma-aminobutyric acid transporter. J Biol Chem, 282 (21): 15528-33. [PMID:17400549]

11. Fülep GH, Hoesl CE, Höfner G, Wanner KT. (2006) 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. Eur J Med Chem, 41 (7): 809-24. [PMID:16766089]

12. Han X, Patters AB, Jones DP, Zelikovic I, Chesney RW. (2006) The taurine transporter: mechanisms of regulation. Acta Physiol (Oxf), 187 (1-2): 61-73. [PMID:16734743]

13. Knutsen LJ, Andersen KE, Lau J, Lundt BF, Henry RF, Morton HE, Naerum L, Petersen H, Stephensen H, Suzdak PD et al.. (1999) Synthesis of novel GABA uptake inhibitors. 3. Diaryloxime and diarylvinyl ether derivatives of nipecotic acid and guvacine as anticonvulsant agents. J Med Chem, 42 (18): 3447-62. [PMID:10479278]

14. Kvist T, Christiansen B, Jensen AA, Bräuner-Osborne H. (2009) The four human gamma-aminobutyric acid (GABA) transporters: pharmacological characterization and validation of a highly efficient screening assay. Comb Chem High Throughput Screen, 12 (3): 241-9. [PMID:19275529]

15. Madsen KK, White HS, Schousboe A. (2010) Neuronal and non-neuronal GABA transporters as targets for antiepileptic drugs. Pharmacol Ther, 125 (3): 394-401. [PMID:20026354]

16. Schousboe A, Madsen KK, White HS. (2011) GABA transport inhibitors and seizure protection: the past and future. Future Med Chem, 3 (2): 183-7. [PMID:21428813]

17. Schousboe A, Sarup A, Larsson OM, White HS. (2004) GABA transporters as drug targets for modulation of GABAergic activity. Biochem Pharmacol, 68 (8): 1557-63. [PMID:15451399]

18. Semyanov A, Walker MC, Kullmann DM, Silver RA. (2004) Tonically active GABA A receptors: modulating gain and maintaining the tone. Trends Neurosci, 27 (5): 262-9. [PMID:15111008]

19. Thomsen C, Sørensen PO, Egebjerg J. (1997) 1-(3-(9H-carbazol-9-yl)-1-propyl)-4-(2-methoxyphenyl)-4-piperidinol, a novel subtype selective inhibitor of the mouse type II GABA-transporter. Br J Pharmacol, 120 (6): 983-5. [PMID:9134205]

20. White HS, Watson WP, Hansen SL, Slough S, Perregaard J, Sarup A, Bolvig T, Petersen G, Larsson OM, Clausen RP et al.. (2005) First demonstration of a functional role for central nervous system betaine/{gamma}-aminobutyric acid transporter (mGAT2) based on synergistic anticonvulsant action among inhibitors of mGAT1 and mGAT2. J Pharmacol Exp Ther, 312 (2): 866-74. [PMID:15550575]

Stefan Bröer Research School of Biology Australian National University Linnaeus Way 134 Canberra, ACT, 0200 Australia