Subthreshold changes of voltage-dependent activation of the K(V)7.2 channel in neonatal epilepsy.
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.
Hunter
Jessica
J
Department of Human Genetics, Emory University, 615 Michael Street, Whitehead Building, Suite 301, Atlanta, Georgia 30322, USA.
Maljevic
Snezana
S
Shankar
Anupama
A
Siegel
Anne
A
Weissman
Barbara
B
Holt
Philip
P
Olson
Larry
L
Lerche
Holger
H
Escayg
Andrew
A
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
D004247:DNA; D051658:KCNQ2 Potassium Channel; C496915:Kcnq2 protein, rat; D012313:RNA