PROPERTIES OF NEURONAL NICOTINIC ACETYLCHOLINE-RECEPTOR MUTANTS FROM HUMANS SUFFERING FROM AUTOSOMAL-DOMINANT NOCTURNAL FRONTAL-LOBE EPILEPSY

1 Physiological and pharmacological properties of the human neuronal a lpha 4 beta 2 nicotinic AChR and mutants found in patients suffering f rom autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) were s tudied. 2 Investigations of nicotinic AChRs reconstituted in Xenopus o ocytes with the control or mutated alpha 4 subunits revealed that both mutation S248F as well as the Leucine insertion (776ins3) result in m ajor but different changes in the physiological and pharmacological pr operties of the receptors. 3 Mutation S248F causes a decrease in appar ent affinity to ACh of about 7 fold. In addition, this receptor alread y desensitizes during exposure to agonist concentration 3000 times low er than the control. 4 776ins3 provokes a 10 fold increase of apparent ACh affinity, an increase in the IC50 caused by prolonged ACh exposur es and a slowing down of the response decay. 5 At saturating ACh conce ntration cells expressing the S248F mutant display average currents th at are about five times smaller than control. 6 When measured at very low concentration, agonist sensitivities of the control and mutated re ceptors to ACh, nicotine and epibatidine exhibit differences that matc h those observed for higher agonist concentrations. 7 Mutation 776ins3 increases the apparent efficacy to cytisine. 8 Data presented herein suggest that mutation S248F mainly affects the desensitization propert ies of the receptor while the leucine insertion (776ins3) increases th e probability of transition to the active state. Although these mutati ons differentially affect the receptor properties they both result in reduced permeability to calcium and enhanced desensitization sensitivi ty that might account for the ADNFLE phenotype.