INHIBITION OF MUSCLE ACETYLCHOLINE RECEPTOR BY THE ANTIEPILEPTIC DRUG LAMOTRIGINE

VALLÉS ANA SOFIA; GARBUS I; BARRANTES FJ

Bariloche, Rio Negro, Argentina

Congreso; BARILOCHE PROTEIN SYMPOSIUM ARGENTINE SOCIETY FOR BIOCHEMISTRY AND MOLECULAR BIOLOGY XXXIX ANNUAL MEETING.Sociedad Argentina de Biofísica; 2003

Some forms of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) have been found to be associated with genes coding for the alpha4 beta2 neuronal acetylcholine receptor (AChR). Lamotrigine (LTG) is a triazine compound chemically unrelated to other antiepileptic drugs. Its major mechanism of action is blocking the voltage-dependent sodium-channel conductance. Here we characterized the effect of LTG on the muscle AChR heterologously expressed in CHOK1/A5 cells by recording the single-channel activity of the receptor using the patch-clamp technique. LTG was found to alter AChR channel kinetics. Exposure to the drug 1) diminished the channel amplitude; 2) caused shortening of the channel open state; 3) increased burst duration, 4) increased the duration and area of the briefest component of the channel closed state. In the concentration range tested (50-150 microM), the effects did not depend on the dose. We propose that LTG blocks the AChR allowing it to reopen quickly, through a mechanism that is compatible with that of open channel blockers. Work supported in part by grants from UNS and FONCYT (LTG) is a triazine compound chemically unrelated to other antiepileptic drugs. Its major mechanism of action is blocking the voltage-dependent sodium-channel conductance. Here we characterized the effect of LTG on the muscle AChR heterologously expressed in CHOK1/A5 cells by recording the single-channel activity of the receptor using the patch-clamp technique. LTG was found to alter AChR channel kinetics. Exposure to the drug 1) diminished the channel amplitude; 2) caused shortening of the channel open state; 3) increased burst duration, 4) increased the duration and area of the briefest component of the channel closed state. In the concentration range tested (50-150 microM), the effects did not depend on the dose. We propose that LTG blocks the AChR allowing it to reopen quickly, through a mechanism that is compatible with that of open channel blockers. Work supported in part by grants from UNS and FONCYT (LTG) is a triazine compound chemically unrelated to other antiepileptic drugs. Its major mechanism of action is blocking the voltage-dependent sodium-channel conductance. Here we characterized the effect of LTG on the muscle AChR heterologously expressed in CHOK1/A5 cells by recording the single-channel activity of the receptor using the patch-clamp technique. LTG was found to alter AChR channel kinetics. Exposure to the drug 1) diminished the channel amplitude; 2) caused shortening of the channel open state; 3) increased burst duration, 4) increased the duration and area of the briefest component of the channel closed state. In the concentration range tested (50-150 microM), the effects did not depend on the dose. We propose that LTG blocks the AChR allowing it to reopen quickly, through a mechanism that is compatible with that of open channel blockers. Work supported in part by grants from UNS and FONCYT