Lamotrigine activates the nicotinic acetylcholine receptor through an agonist-independent site of action

SOFIA VALLES, ANA; GARBUS INGRID,; ANTOLLINI SILVIA,; BARRANTES FRANCISCO

Cancun

Congreso; 21st Biennial Meeting of the International Society for Neurochemistry y 38th Annual Meeting of the American Society for Neurochemistry; 2007

International Society of Neurochemistry (ISN) and American Society of Neurochemistry (ASN).

Lamotrigine (LTG) is an antiepileptic drug employed in thetreatment of partial epilepsies. We studied its possibleinteraction with channels other than its known therapeutictarget, the voltage-gated sodium channel, using the adultmuscle nicotinic acetylcholine receptor (AChR) as a model.Patch-clamp recordings showed that LTG (50?400 mM)affected AChR channel function, behaving as an open-channelblocker when co-applied with the natural agonist, acetylcholine(Valle´ s et al., Neuro Report 2007; 18, 45?50). Here, singlechannelrecordings with LTG alone demonstrate that LTG(0.05?100 mM) is able to activate the AChR channel by itself.[125I]a-bungarotoxin binding studies further indicate that LTGdoes not bind to the ACh binding site. Moreover, fluorescenceexperiments using the probe crystal violet, which displayshigher affinity for the desensitized (D, in the presence ofagonist) than for the resting AChR conformation (R, in theabsence of agonist) show that LTG is able to induce thetransition from the R-state to the D-state in the presence of abungarotoxin,i.e. when the canonical agonist binding site isblocked. We conclude that LTG displays dual agonist /channelblocker activities on the AChR, operating through differentsites.