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

Eur J Pharmacol. 2004 Oct 1;500(1-3):281-7. doi: 10.1016/j.ejphar.2004.07.032.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Anticonvulsants / pharmacology*
  • Carrier Proteins / antagonists & inhibitors*
  • Carrier Proteins / metabolism
  • Epilepsy / drug therapy*
  • Epilepsy / metabolism
  • GABA Plasma Membrane Transport Proteins / chemistry
  • GABA Plasma Membrane Transport Proteins / metabolism
  • Humans
  • Isoxazoles / pharmacology
  • Membrane Transport Modulators / metabolism
  • Membrane Transport Modulators / pharmacology

Substances

  • Anticonvulsants
  • Carrier Proteins
  • EF1502
  • GABA Plasma Membrane Transport Proteins
  • Isoxazoles
  • Membrane Transport Modulators
  • SLC6A1 protein, human
  • betaine plasma membrane transport proteins