Mutated nicotinic receptors responsible for autosomal dominant nocturnal frontal lobe epilepsy are more sensitive to carbamazepine.

Abstract

The recent linkage between a genetically transmissible form of epilepsy (ADNFLE) and mutations within the alpha4 subunit, one component of the major brain neuronal nicotinic acetylcholine receptor (nAChR), raises the question of the role of this receptor in epileptogenesis. Although acting by different mechanisms, the two genetic alterations so far identified both render the nAChR less efficient. In view of the high sensitivity of ADNFLE to carbamazepine (CBZ), we studied the effects of this drug and of valproate (VPA) on the human alpha4beta2 nAChR and its mutations. The alpha4beta2 nAChRs from control and mutant alpha4 subunits were reconstituted in Xenopus oocytes and investigated by using a dual-electrode voltage clamp technique. Acetylcholine (ACh)-evoked currents recorded in the absence or presence of antiepileptic drugs (AEDs) were studied to analyze the mode of action of these compounds. ACh-evoked currents at the human alpha4beta2 nAChR were readily and reversibly inhibited by approximately 100 microM CBZ. This compound was found to be a noncompetitive inhibitor of the nAChR, which probably acts by entering the channel and causing a blockade by steric hindrance. Dose-response inhibition curves determined on the control receptor and on ADNFLE-mutant receptors showed a greater sensitivity of the mutants to CBZ, with median inhibitory concentrations (IC50s) in the range of the antiepileptic plasma levels of CBZ. In contrast, VPA had nearly no effect on control and mutant nAChRs. CBZ inhibits the neuronal alpha4beta2 nAChRs at pharmacologic concentrations, with ADNFLE mutants displaying about threefold higher sensitivity to this compound. The increased sensitivity of these mutant receptors supports the hypothesis that the antiepileptic activity of CBZ can, at least to some extent, be attributed to the nAChR inhibition.