Role of the betaine/GABA transporter (BGT-1/GAT2) for the control of epilepsy.

Inactivation of gamma-aminobutric acid (GABA) as a neurotransmitter is mediated by diffusion in the synaptic cleft followed by binding to transporter sites and translocation into the intracellular compartment. The GABA transporters of which four subtypes have been cloned (GAT1-4) are distributed at presynaptic nerve endings as well as extrasynaptically on astrocytic and neuronal elements. This anatomical arrangement of the transporters appears to be of critical functional importance for the maintenance of GABAergic neurotransmission. Pharmacological characterization of the GABA transporters using a large number of GABA analogs having restricted conformation and lipophilic character has been of instrumental importance for elucidation of the functional importance of the different transporters. One such analog EF1502 (N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-hydroxy-4-methylamino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol) has been shown to selectively inhibit GAT1 (GABA transporter 1) and GAT2/BGT-1 (betaine/GABA transporter). Moreover, this GABA analog exhibits an unusually high efficiency as an anticonvulsant suggesting a novel role of the betaine/GABA transporter in epileptic seizure control. It is hypothesized that extrasynaptic actions of GABA may be involved in this phenomenon.