Research Project
2269801
DESCRIPTION: (Adapted from the applicant's abstract) GABA transport inhibitors have recently shown promise as anticonvulsants. The cloning of two novel GABA transporters, in addition to the previously cloned neuronal transporter, suggests a diversity of therapeutic targets. However, it is not known whether an effective drug should be a substrate for the transporter, or should simply bind but not be transported. Due to the electrogenic properties of these transporters, transport of substrate is associated with membrane depolarization. Measurements of membrane voltage during transport allow one to distinguish between substrate and non-substrate inhibitors. During Phase I the applicants shall establish a fluorescent assay for transport utilizing voltage-sensitive dyes, using the neuronal transporter designated GAT-1. This methodology will allow a rapid screening assay for newly synthesized drugs, and will provide information as to their mechanism of action. In Phase II, they will extend these studies to the two novel transporters, and will also test selective compounds in animal models of epilepsy.
