title: Benign familial neonatal convulsions caused by altered gating of KCNQ2/KCNQ3 potassium channels.
abstract: The muscarinic-regulated potassium current (M-current), formed by the heteromeric assembly of subunits encoded by the KCNQ2 and KCNQ3 genes, is a primary regulator of neuronal excitability; this regulation is accomplished by impeding repetitive firing and causing spike-frequency adaptation. Mutations in KCNQ2 or KCNQ3 cause benign familial neonatal convulsions (BFNC), a rare autosomal-dominant generalized epilepsy of newborns, by reducing the maximal current carried by the M-channels without affecting ion selectivity or gating properties. Here we show that KCNQ2/KCNQ3 channels carrying a novel BFNC-causing mutation leading to an arginine to tryptophan substitution in the voltage-sensing S4 domain of KCNQ2 subunits (R214W) displayed slower opening and faster closing kinetics and a decreased voltage sensitivity with no concomitant changes in maximal current or plasma membrane expression. These results suggest that mutation-induced gating alterations of the M-current may cause epilepsy in neonates.
authors.affiliation: Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, 80131 Naples, Italy.
authors.forename: Pasqualina
authors.initials: P
authors.lastname: Castaldo
authors.forename: Emanuele Miraglia
authors.initials: EM
authors.lastname: del Giudice
authors.forename: Giangennaro
authors.initials: G
authors.lastname: Coppola
authors.forename: Antonio
authors.initials: A
authors.lastname: Pascotto
authors.forename: Lucio
authors.initials: L
authors.lastname: Annunziato
authors.forename: Maurizio
authors.initials: M
authors.lastname: Taglialatela
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D020936:Epilepsy, Benign Neonatal / Q000453:epidemiology / Q000209:etiology* / Q000503:physiopathology*; D015870:Gene Expression; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D007558:Italy / Q000453:epidemiology; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D008845:Microinjections; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010375:Pedigree; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D017434:Protein Structure, Tertiary / Q000502:physiology; D021122:Protein Subunits; D013329:Structure-Activity Relationship; D014981:Xenopus
chemical_list: D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; D051659:KCNQ3 Potassium Channel; C496916:KCNQ3 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D021122:Protein Subunits; D011188:Potassium