Dual agonist-channel blocker activity of Lamotrigine on the nicotinic acetylcholine receptor.

VALL¨¦S, A. S.; GARBUS, I.; ANTOLLINI, S. S.; BARRANTES, F. J.

Rosario, Santa Fe, Argentina

Congreso; XLII Reunión Anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2006

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular

Lamotrigine (LTG) is an antiepileptic drug employed in the treatment of partial epilepsies. We studied its possible interaction with channels other than its known therapeutic target, the voltage gated sodium channel, using the adult muscle nicotinic acetylcholine receptor (AChR) as a model. Patch-clamp recordings showed that LTG (50-400 ¦ÌM) affected AChR channel function, behaving as an open-channel blocker when co-applied with the natural agonist, acetylcholine (Vall¨¦s et al., NeuroReport 2006, in press). Here, single-channel recordings with LTG alone demonstrate that LTG (0.05-100 ¦ÌM) is able to activate the AChR channel by itself. [125I]-a-bungarotoxin binding studies further indicate that LTG does not bind to the ACh binding side. Moreover, fluorescence experiments using the probe crystal violet, which displays higher affinity for the desensitized (D, in the presence of agonist) than for the resting AChR conformation (R, absence of agonist) show that LTG is able to induce the transition from the R-state to the D-state in the presence of a-bungarotoxin, i.e. when the canonical agonist binding site is blocked. We concluded that LTG displays dual agonist/channel blocker activities on AChR, which operate through different sites.