Properties of neuronal nicotinic acetylcholine receptor mutants from humans suffering from autosomal dominant nocturnal frontal lobe epilepsy
Version of Record online: 3 FEB 2009
1998 British Pharmacological Society
British Journal of Pharmacology
Volume 125, Issue 4, pages 751–760, October 1998
How to Cite
Bertrand, S., Weiland, S., Berkovic, S. F., Steinlein, O. K. and Bertrand, D. (1998), Properties of neuronal nicotinic acetylcholine receptor mutants from humans suffering from autosomal dominant nocturnal frontal lobe epilepsy. British Journal of Pharmacology, 125: 751–760. doi: 10.1038/sj.bjp.0702154
- Issue online: 3 FEB 2009
- Version of Record online: 3 FEB 2009
- (Received February 10, 1998, Revised July 31, 1998, Accepted August 8, 1998)
- 1Physiological and pharmacological properties of the human neuronal α4β2 nicotinic AChR and mutants found in patients suffering from autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) were studied.
- 2Investigations of nicotinic AChRs reconstituted in Xenopus oocytes with the control or mutated α4 subunits revealed that both mutation S248F as well as the Leucine insertion (776ins3) result in major but different changes in the physiological and pharmacological properties of the receptors.
- 3Mutation S248F causes a decrease in apparent affinity to ACh of about 7 fold. In addition, this receptor already desensitizes during exposure to agonist concentration 3000 times lower than the control.
- 4776ins3 provokes a 10 fold increase of apparent ACh affinity, an increase in the IC50 caused by prolonged ACh exposures and a slowing down of the response decay.
- 5At saturating ACh concentration cells expressing the S248F mutant display average currents that are about five times smaller than control.
- 6When measured at very low concentration, agonist sensitivities of the control and mutated receptors to ACh, nicotine and epibatidine exhibit differences that match those observed for higher agonist concentrations.
- 7Mutation 776ins3 increases the apparent efficacy to cytisine.
- 8Data presented herein suggest that mutation S248F mainly affects the desensitization properties of the receptor while the leucine insertion (776ins3) increases the probability of transition to the active state. Although these mutations differentially affect the receptor properties they both result in reduced permeability to calcium and enhanced desensitization sensitivity that might account for the ADNFLE phenotype.
British Journal of Pharmacology (1998) 125, 751–760; doi:10.1038/sj.bjp.0702154