Overview: Plasma membrane-located GABA transporters (provisional nomenclature as adopted for human GABA transporters) are members of the solute carrier family 6 (SLC6) of sodium- and chloride-dependent neurotransmitter receptor transporters that includes the monoamine and glycine transporters (Chen et al., 2004). The members of this superfamily share a structural motif of 12 TM segments (Palacín et al., 1998) that has been confirmed by the crystal structure of a bacterial homolog (LeuTAa) of the Na+/Cl--dependent neurotransmitter transporters from Aquiflex aeolicus (Yamashita et al., 2005). The activity of GABA-transporters located upon both neurones and glia 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 GABAA receptors in certain neuronal populations (Semyanov et al., 2004). A structurally and functionally distinct vesicular transporter representing the SCL32 family [VGAT/VIAAT (ENSG00000101438); McIntire et al., 1997; Sagne et al., 1997; Gasnier, 2004], subject to inhibition by vigabatrin, is responsible for concentrating GABA (and glycine) within synaptic vesicles.
| Nomenclature | GAT-1 | GAT-2 | GAT-3 | BGT-1 |
| Other names | mGAT-1, SLC6A1 | mGAT3, SLC6A16 | mGAT4, GAT-B, SLC6A11 | mGAT2, SLC6A12 |
| Ensembl ID | ENSG00000157103 | ENSG00000010379 | ENSG00000132164 | ENSG00000111181 |
| Endogenous substrates | GABA | GABA, β-alanine | GABA, β-alanine | GABA, betaine |
| Selective inhibitors (IC50) | NNC-711 (0.04 µM), SKF89976A (0.13 µM), CI-966 (0.26 µM), tiagabine (0.8 µM), EF1500 (2 µM) (R)-EF1502 (4 µM), LU32176B (4 µM), (S)-EF1502 (120 µM) | – | SNAP-5114 (6.6 µM) | NNC052090 (1.4 µM), (R)-EF1502 (22 µM), (S)-EF1502 (34 µM), LU 32176B (>100 µM) |
| Probes | [3H]Tiagabine | – | – | – |
| Stoichiometry | 2 Na+: 1 Cl-: 1 GABA | – | ≥2 Na+: 2 Cl-: 1 GABA | 3 Na+: 1 (or 2) Cl-: 1 GABA |
SNAP-5114 is only weakly selective for GAT-3, with IC50 values in the range 20 to >30 µM at GAT-1, GAT-2 and BGT-1, whereas NNC052090 has at least an order of magnitude selectivity for BGT-1 [see Schousboeet al. (2004a) and Clausen et al. (2006) for reviews]. (R)-(1-{2-[tris(4-methoxyphenyl)methoxy]ethyl}pyrrolidin-2-yl)acetic acid is a recently described compound that displays 20-fold selectivity for GAT-3 over GAT-1 (Fülep et al., 2006). In addition to the inhibitors listed, EGYT3886 is a moderately potent, although non-selective, inhibitor of all cloned GABA transporters (IC50= 26–46 µM; Dhar et al., 1994). Diaryloxime and diarylvinyl ether derivatives of nipecotic acid and guvacine that potently inhibit the uptake of [3H]GABA into rat synaptosomes have been described (Knutsen et al., 1999). 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 Schousboe et al. (2004b) and Clausen et al. (2006) for reviews]. GAT-3 is inhibited by physiologically relevant concentrations of Zn2+ (Cohen-Kfir et al., 2005).
Glossary
Abbreviations:
- CI966
[1-[2-[bis-4(trifluromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid
- EF1500
N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-hydroxy-4-amino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol
- EF1502
N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-hydroxy-4-(methylamino)4,5,6,7,tetrabenzo[d]isoxazol-3-ol
- EGYT3886
(-)-2-phenyl-2-[(dimethylamino)ethoxy]-(1R)-1,7,7-trimethylbicyclo[2.2.1]heptane; exo-THPO, 3-hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazol
- LU32-176B
N-[4,4-bis(4-fluorophenyl)-butyl]-3-hydroxy-4-amino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol
- NNC711
1-2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride
- NNC052090
1-(3-(9H-carbazol-9-yl)-1-propyl)-4-(2-methoxyphenyl)-4-piperidinol
- SKF89976A
1-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid
Further Reading
Clausen RP, Madsen K, Larsson OM, Frolund B, Krogsgaard-Larsen P, Schousboe A (2006). Structure-activity relationship and pharmacology of gamma-aminobutyric acid (GABA) transport inhibitors. Adv Pharmacol54: 265–284.
Chen N-H, Reith MEA, Quick MW (2004). Synaptic uptake and beyond: the sodium and chloride dependent neurotransmitter transporter family SLC6. Pflügers Archiv447: 519–531.
Dalby NO (2003). Inhibition of gamma-aminobutyric acid uptake: anatomy, physiology and effects against epileptic seizures. Eur J Pharmacol479: 127–137.
Gadia A, Lopez-Colome AM (2001). Glial transporters for glutamate, glycine and GABA: II. GABA transporters. J Neurosci Res63: 461–468.
Gasnier B (2004). The SLC32 transporter, a key protein for the synaptic release of inhibitory amino acids. Pflügers Archiv447: 756–759.
Hog S, Greenwood JR, Madsen KB, Larsson OM, Frolund B, Schousboe A et al. (2006). Structure-activity relationships of selective GABA uptake inhibitors. Curr Top Med Chem6: 1861–1882.
Kanner BI (2006) Structure and function of sodium-coupled GABA and glutamate transporters. J Membr Biol213: 89–100.
Kulig K, Szwaczkiewicz M (2008). The role of structure activity relationship studies in the search for new GABA uptake inhibitors. Mini Rev Med Chem8: 1214–1223.
Palacín M, Estévez R, Bertran J, Zorano A (1998). Molecular biology of mammalian plasma membrane amino acid transporters Physiol Rev78: 969–1054.
Richerson GB, Wu Y (2004). Role of the GABA transporter in epilepsy. Adv Exp Med Biol548: 76–91.
Sarup A, Larsson OM, Schousboe A (2003). GABA Transporters and GABA-Transaminase as Drug Targets. Curr Drug Target CNS Neurol Disord2: 269–277.
Schousboe A, Sarup A, Larsson OM, White HS (2004a). GABA transporters as drug targets for modulation of GABAergic activity. Biochem Pharmacol68: 1557–1563.
Schousboe A, Sarup A, Bak LK, Waagepetersen HS, Larsson OM (2004b). Role of astrocytic transport processes in glutamatergic and GABAergic neurotransmission. Neurochem Int45: 521–527.
Semyanov A, Walker MC, Kullmann DM, Silver RA (2004). Tonically active GABAA receptors: modulating gain and maintaining the tone. Trends Neurosci27: 262–269.
Soudijn W, van Wijngaarden I (2000). The GABA transporter and its inhibitors. Curr Med Chem7: 1063–1079.
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