Mutation (Ser284Leu) of neuronal nicotinic acetylcholine receptor α4 subunit associated with frontal lobe epilepsy causes faster desensitization of the rat receptor expressed in oocytes

Abstract To date five mutations in two major constituents of neuronal nicotinic acetylcholine receptor (nAChR) in the brain, i.e. α4 and β2 subunits, have been identified to be associated with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Among them, only Ser284Leu, a point mutation in α4 subunit identified in ADNFLE as well as in a sporadic case with nocturnal frontal lobe epilepsy, remains to be characterized electrophysiologically. We examined the properties of rat nAChR harboring Ser284Leu reconstituted on Xenopus oocytes. Currents elicited in response to application of acetylcholine to oocytes expressing wild type or mutant nAChR were measured by a standard two-microelectrode voltage clamp method. Compared with wild-type nAChR, the mutant nAChR had a comparable EC 50 value for acetylcholine whereas it showed faster desensitization and lower Cs + /Na + permeability ratio. Ser284Phe, a putative mutation constructed for comparison, exhibited similar properties. These findings indicate that Ser 284 plays an important role in gating of nAChR along with Thr 276 and Ser 280 , and suggest that mutation at Ser 284 could reduce nAChR activity similar to other mutations of α4 subunit found in ADNFLE.