Schroeder B C, Kubisch C, Stein V, Jentsch T J
Zentrum für Molekulare Neurobiologie Hamburg, Universität Hamburg, Germany.
Nature. 1998 Dec 17;396(6712):687-90. doi: 10.1038/25367.
Epilepsy affects more than 0.5% of the world's population and has a large genetic component. It is due to an electrical hyperexcitability in the central nervous system. Potassium channels are important regulators of electrical signalling, and benign familial neonatal convulsions (BFNC), an autosomal dominant epilepsy of infancy, is caused by mutations in the KCNQ2 or the KCNQ3 potassium channel genes. Here we show that KCNQ2 and KCNQ3 are distributed broadly in brain with expression patterns that largely overlap. Expression in Xenopus oocytes indicates the formation of heteromeric KCNQ2/KCNQ3 potassium channels with currents that are at least tenfold larger than those of the respective homomeric channels. KCNQ2/KCNQ3 currents can be increased by intracellular cyclic AMP, an effect that depends on an intact phosphorylation site in the KCNQ2 amino terminus. KCNQ2 and KCNQ3 mutations identified in BFNC pedigrees compromised the function of the respective subunits, but exerted no dominant-negative effect on KCNQ2/KCNQ3 heteromeric channels. We predict that a 25% loss of heteromeric KCNQ2/KCNQ3-channel function is sufficient to cause the electrical hyperexcitability in BFNC. Drugs raising intracellular cAMP may prove beneficial in this form of epilepsy.
癫痫影响着全球超过0.5%的人口，且具有很大的遗传因素。它是由中枢神经系统的电活动过度兴奋引起的。钾通道是电信号的重要调节因子，良性家族性新生儿惊厥（BFNC）是一种常染色体显性遗传性婴儿癫痫，由KCNQ2或KCNQ3钾通道基因突变引起。我们在此表明，KCNQ2和KCNQ3在大脑中广泛分布，其表达模式在很大程度上重叠。在非洲爪蟾卵母细胞中的表达表明形成了异源KCNQ2/KCNQ3钾通道，其电流比各自的同源通道至少大十倍。KCNQ2/KCNQ3电流可被细胞内的环磷酸腺苷（cAMP）增强，这种效应依赖于KCNQ2氨基末端完整的磷酸化位点。在BFNC家系中鉴定出的KCNQ2和KCNQ3突变损害了各自亚基的功能，但对KCNQ2/KCNQ3异源通道没有显性负效应。我们预测，异源KCNQ2/KCNQ3通道功能丧失25%就足以导致BFNC中的电活动过度兴奋。提高细胞内cAMP水平的药物可能对这种形式的癫痫有益。
