GABA transporter

GABA transporter GAT1 (SLC6A1) GABAergic neurons in CNS <10 Clearance of interstitial neurotransmitter, reuptake into neurons Tiagabine, an antiepileptic drug... 

Vesicular GABA transporter vesicular inhibitory amino acid transporte. 

The removal of released DA from the synaptic extracellular space to facilitate its intraneuronal metabolism is achieved by a membrane transporter that controls the synaptic concentration. This transporter has been shown to be a 619 amino-acid protein with 12 hydrophobic membrane spanning domains (see Giros and Caron 1993). Although it has similar amino-acid sequences to that of the NA (and GABA) transporter, there are sufficient differences for it to show some specificity. Thus DA terminals will not concentrate NA and the DA transporter is blocked by a drug such as nomifensine which has less effect on NA uptake. Despite this selectivity some compounds, e.g. amphetamine and 6-OHDA (but not MPTP), can be taken up by both neurons. The role of blocking DA uptake in the central actions of cocaine and amphetamine is considered later (Chapter 23). 

Figure 11.4 Blockers of GABA transport.The upper panel shows the structure of several GABA analogues that inhibit GABA transport into neurons or glia (see text). The lower panels show more recently developed compounds that exhibit selectivity for various cloned GABA transporters...

Mclntire, SF, Reimer, RJ, Schuske, K, Edwards, RH and Jorgensen, EM (1997) Identification and characterization of the vesicular GABA transporter. Nature 389 870-876. 

An example of transporter identification in a complex case the three GABA transport systems of Saccharomyces cerevisiae... 

Following the release of dopamine, the primary mode of removal from the synapse is reuptake into the presynaptic neuron via the dopamine transporter (DAT). DAT is dependent upon the energy created by the Na+/K+ pump and is a member of the Na+/Cl -dependent plasma membrane transporter family, as are the norepinephrine and 7-aminobutyric acid (GABA) transporters. Imaging studies utilizing compounds with highly specific affinity for DAT... 

Twaites, D. T., Basterfield, L., McCleave, P. M. J., Carter, S. M., and Simmons, N. L., Gamma-aminobutyric acid (GABA) transport across human intestinal epithelial (Caco-2) cell monolayers, Brit.J. Pharmacol. 2000, 129, 457-464. 

Deken, S. L., Wang, D. and Quick, M. W. Plasma membrane GABA transporters reside on distinct vesicles and undergo rapid regulated recycling. /. Neurosci. 23 1563-1568, 2003. 

Schousboe, A, Sarup, A., Larsson, O. M. and White, H. S. GABA transporters as drug targets for modulation of GABAergic activity. Biochem. Pharmacol. 68 1557-1563. 

Mager, S Naeve, J., Quick, M., Labarca, C., Davidson, N., and Lester, H. A. (1993) Steady states, charge movements, and rates for a cloned GABA transporter expressed in Xenopus oocytes. Neuron 10,177-188. 

Scholze, P, Freissmuth, M., and Sitte, H. H. (2002) Mutations within an intramembrane leucine heptad repeat disrupt oligomer formation of the rat gaba transporter 1. J. Biol. Chem. 277,43682 13690. 

Fig. 1. Chemical structures of some common GABA mimitics of restricted comformation that bind to the substrate binding sites in the GABAa receptor complex and the GABA transporters, respectively.

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