Nicotinic receptor mutations in human epilepsy

Abstract

Publisher Summary Mutations within the genes coding for the α 4- and β 2-subunits (CHRNA4 and CHRNB2) of the neuronal nicotinic acetylcholine receptor (nAChR) are found in families with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Each mutation in the highly conserved pore-lining second transmembrane region (TM2) region of α 4 exhibits its own specific electro-physiological properties. The α 4-Ser248Phe mutation has profound effects on the function of the receptor. Electrophysiological experiments demonstrated an increase of the desensitization rate, followed by a prolonged resensitization period; both effects are probably due to a destabilization of the ion channels open configuration. The second ADNFLE mutation, α 4-776ins3, increases the receptors' apparent affinity for acetylcholine (ACh), and reduces the Ca 2+ -permeability, but has only minor effects on the receptor desensitization. Despite these differences, the main effect of both mutations is a reduced Ca 2+ influx, which could be interpreted as a loss-of-function effect.