期刊
JOURNAL OF NEUROSCIENCE
卷 27, 期 18, 页码 4919-4928出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0580-07.2007
关键词
epilepsy; potassium channels; KCNQ2 subunits; benign familial neonatal convulsions; channel gating; mutations
资金
- NINDS NIH HHS [R01 NS043394] Funding Source: Medline
- Telethon [GGP030209] Funding Source: Medline
Heteromeric assembly of KCNQ2 and KCNQ3 subunits underlie the M-current (I-KM), a slowly activating and noninactivating neuronal K+ current. Mutations in KCNQ2 and KCNQ3 genes cause benign familial neonatal convulsions (BFNCs), a rare autosomal-dominant epilepsy of the newborn. In the present study, we describe the identification of a novel KCNQ2 heterozygous mutation (c587t) in a BFNC-affected family, leading to an alanine to valine substitution at amino acid position 196 located at the N-terminal end of the voltage-sensing S-4 domain. The consequences on KCNQ2 subunit function prompted by the A196V substitution, as well as by the A196V/L197P mutation previously described in another BFNC-affected family, were investigated by macroscopic and single-channel current measurements in CHO cells transiently transfected with wild-type and mutant subunits. When compared with KCNQ2 channels, homomeric KCNQ2 A196V or A196V/L197P channels showed a 20 mV rightward shift in their activation voltage dependence, with no concomitant change in maximal open probability or single-channel conductance. Furthermore, current activation kinetics of KCNQ2 A196V channels displayed an unusual dependence on the conditioning prepulse voltage, being markedly slower when preceded by prepulses to more depolarized potentials. Heteromeric channels formed by KCNQ2A196V and KCNQ3 subunits displayed gating changes similar to those of KCNQ2 A196V homomeric channels. Collectively, these results reveal a novel role for noncharged residues in the N-terminal end of S-4 in controlling gating of I-KM and suggest that gating changes caused by mutations at these residues may decrease I-KM function, thus causing neuronal hyperexcitability, ultimately leading to neonatal convulsions.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据