title: Subthreshold changes of voltage-dependent activation of the K(V)7.2 channel in neonatal epilepsy.
abstract: Benign familial neonatal convulsions (BFNC) is an epileptic disorder caused by dominant mutations in the genes KCNQ2 and KCNQ3 encoding the K+ channels K(V)7.2 and K(V)7.3. We identified two novel KCNQ2 mutations in two BFNC families. One mutation predicted a truncated protein (S247X) that lacks the channel's pore region, the other resulted in the amino acid substitution S122L in the S2 segment of K(V)7.2. In comparison to wild-type (WT) K(V)7.2, functional analysis of S122L mutant channels in Xenopus oocytes revealed a significant positive shift and increased slope of the activation curve leading to significant current reduction in the subthreshold range of an action potential (75% reduction at -50 mV). Our results establish an important role of the K(V)7.2 S2 segment in voltage-dependent channel gating and demonstrate in a human disease that subthreshold voltages are likely to represent the physiologically relevant range for this K+ channel to regulate neuronal firing.
authors.affiliation: Department of Human Genetics, Emory University, 615 Michael Street, Whitehead Building, Suite 301, Atlanta, Georgia 30322, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hunter
authors.forename: Snezana
authors.initials: S
authors.lastname: Maljevic
authors.forename: Anupama
authors.initials: A
authors.lastname: Shankar
authors.forename: Anne
authors.initials: A
authors.lastname: Siegel
authors.forename: Barbara
authors.initials: B
authors.lastname: Weissman
authors.forename: Philip
authors.initials: P
authors.lastname: Holt
authors.forename: Larry
authors.initials: L
authors.lastname: Olson
authors.forename: Holger
authors.initials: H
authors.lastname: Lerche
authors.forename: Andrew
authors.initials: A
authors.lastname: Escayg
mesh_terms: D000818:Animals; D051381:Rats; D000595:Amino Acid Sequence; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D004594:Electrophysiology; D020936:Epilepsy, Benign Neonatal / Q000235:genetics / Q000503:physiopathology; D005091:Exons / Q000235:genetics; D005190:Family; D007585:Jews; D051658:KCNQ2 Potassium Channel / Q000235:genetics / Q000502:physiology; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000502:physiology; D009865:Oocytes / Q000502:physiology; D018408:Patch-Clamp Techniques; D010375:Pedigree; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D014982:Xenopus laevis; D006801:Humans
chemical_list: D004247:DNA; D051658:KCNQ2 Potassium Channel; C496915:Kcnq2 protein, rat; D012313:RNA