Felbamate Demonstrates Subunit Selective Activity in Recombinant GABA-A Receptors.
Abstract number :
1.126
Submission category :
Year :
2000
Submission ID :
2628
Source :
www.aesnet.org
Presentation date :
12/2/2000 12:00:00 AM
Published date :
Dec 1, 2000, 06:00 AM
Authors :
Tim A Simeone, Annette M McClellan, Univ of Utah, Salt Lake City, UT.
RATIONALE: Felbamate is used to treat refractory epileptic seizures, and is known to alter several ion channel responses including GABAA receptor-mediated responses. Differences in felbamate potentiation of GABA-mediated responses have been reported for cultured hippocampal and cortical neurons, which may be due to regional distributions of GABAA receptor subunit isoforms. The purpose of this study was to characterize the subunit specificity of felbamate for GABAA receptors. METHODS: Xenopus oocytes were nuclear micro-injected with GABAA receptor subunit cDNA encoding ?(1, 2, 4, or 6), ?(1,2 or 3), and ?(2S or 2L) subunits. After 1-5 days, chloride currents were elicited by exposure to GABA (EC1, 0.1-1?M) or GABA + felbamate (300 ?M). Responses were recorded using two-electrode voltage clamp techniques. RESULTS: Felbamate displayed a wide range of effects across different subunit combinations. Felbamate either potentiated or inhibited chloride currents, depending on GABAA receptor subunit isoform expression. Felbamate enhanced GABA-mediated currently only in ?(1 or 2) ?(2 or 3) ?2S subunit combinations. Receptors containing ?1 subunits were enhanced significantly more than those containing ?2 subunits (37-50% and 19-24% respectively, p<0.01). Inhibition of the current response was observed in all receptors containing ?4, ?1, or ? 2L subunits. Inhibition ranged from 10% (??1?) to nearly 100% (?4?? and ??? 2L). CONCLUSIONS: These results suggest that felbamate modulation of inhibition is highly dependent upon GABAA receptor subunit isoform, for all three subunits (?,?,and ?). The physiological relevance of the dual positive and negative modulation of GABAA receptors is not yet understood. Regional distributions of GABAA receptor isoforms suggest that felbamate may selectively modulate distinct inhibitory circuits. Future experiments will determine the mechanism of action for felbamate, using HEK293 expression systems and rapid ligand exchange techniques. Supported by a EFA Junior Investigator Award and NIH grant 31519.