Gaba Transport A Plasma Membrane GABA Transporters

GABA is actively transported across the plasma membrane by GABA transporters (GATs). The four GATs identified so far (GAT1-3 and GAT4 or BGT-1) belong to the superfamily of Na + - and Cl_-dependent transporters that include transporters for norepinephrine, serotonin, dopamine, and glycine but not for glutamate. The four GATs differ in pharmacology and in cell expression. For instance, GAT1 is inhibited by nipecotic acid and is predominantly found on neurons, although it is also expressed on some glia. GAT2 and GAT3 can transport both GABA and b-alanine. GAT3 is primarily a glial transporter, whereas GAT2 is found on neurons but its cell specificity remains unclear. BGT-1 was first identified in the kidney and transports GABA, betaine, and taurine.

1. Topology

The GATs are glycoproteins with a molecular weight of 70-80 kDa. The presumed topology predicts that both the amino and the carboxy termini are cytoplas-mic and that there are 12 transmembrane domains. The GAT1 topology is illustrated in Fig. 7. There are three glycosylation sites between the third and fourth transmembrane domains. The fourth through sixth extracellular loops form a putative GABA-binding site.

2. Carrier-Mediated Release

The GABA transporters reverse to release cytosolic GABA when the Na + gradient across the membrane is perturbed and also when the membrane potential increases. Although these changes occur rapidly during an action potential, GAT-mediated GABA release (or carrier-mediated release) is probably not a

Figure 7 GAT has 12 transmembrane domains, and both the amino and carboxy termini are intracellular. The putative GABA binding site denoted by asterisks, is on the fourth through sixth extracellular domains.

major route of egress during cell firing because the changes in membrane potential are rapid and transient. However, several studies suggest that activation of the glutamate NMDA receptor causes intracellular Na+ levels to increase sufficiently to produce GAT-mediated GABA release. Small perturbations in the extracellular K+ concentrations, and concomitant membrane depolarization, can also cause carrier-mediated GABA release at levels sufficient to activate nearby GABAa receptors. Seizure activity and the accompanying changes in the extracellular ionic environment may therefore stimulate carrier-mediated GABA release.

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