Functional and pharmacological aspects of GABA transporters

Abstract

Termination of GABAergic neurotransmission is facilitated via high-affinity GABA transporters (GATs), which use the sodium and chloride gradients to drive the active transport of GABA into both the pre- and post-synaptic neurons and neighboring astroglial cells. The GATs are members of the Solute Carrier 6 (SLC6) transporter family. Early pharmacological studies revealed a difference between the uptake specificity between neurons and astrocytes. Moreover, glial transport is preferably inhibited since exclusive inhibition of neuronal GABA transports can lead to seizures in-vivo. Twenty-eight years after the discovery of GABA transporters the first GABA transporter designated GAT1 was cloned. Today, five GABA transporters are known, one of them being the vesicular GABA transporter and the other four GAT1, GAT2, GAT3, and GAT4 are associated with the plasma membrane. The GATs have been extensively characterized pharmacologically. The main emphasis has been put on GAT1 which is the most active among the four GATs. Moreover, a large number of studies have been focused on identifying inhibitors which selectively may inhibit astroglial GABA transport. This is related to the proposal that such inhibitors may be effective anticonvulsants. Subcellular localization studies have shown that the GABA transporters are unevenly distributed within the synapses, GAT1 and GAT4 are primarily located on neurons and astrocytes, respectively and GAT2 and GAT3 are less widely distributed and more diverse. The GAT proteins are composed of 12 transmembrane domains (TMD) and display a high level of homology in their amino acid sequence. Functional analysis has revealed that TMD1, TMD3, Extracellular loop (EL) 2, and EL4 are involved in the binding pocket of GAT1, findings which are confirmed in the bacterial leucine transporter LeuTAa a transporter which shares 20-25 % sequence homology to the SLC transporter family. © 2007 Springer-Verlag US.