Subthreshold changes of voltage-dependent activation of the KV7.2 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 KV7.2 and KV7.3. 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 KV7.2. In comparison to wild-type (WT) KV7.2, 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 KV7.2 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.

Keywords

• BFNC
• Epilepsy
• Ion channel
• Genetics
• Structure function analysis
• Voltage clamp