Yang W P, Levesque P C, Little W A, Conder M L, Ramakrishnan P, Neubauer M G, Blanar M A
Department of Cardiovascular Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
J Biol Chem. 1998 Jul 31;273(31):19419-23. doi: 10.1074/jbc.273.31.19419.
Benign familial neonatal convulsions (BFNC), a class of idiopathic generalized epilepsy, is an autosomal dominantly inherited disorder of newborns. BFNC has been linked to mutations in two putative K+ channel genes, KCNQ2 and KCNQ3. Amino acid sequence comparison reveals that both genes share strong homology to KvLQT1, the potassium channel encoded by KCNQ1, which is responsible for over 50% of inherited long QT syndrome. Here we describe the cloning, functional expression, and characterization of K+ channels encoded by KCNQ2 and KCNQ3 cDNAs. Individually, expression of KCNQ2 or KCNQ3 in Xenopus oocytes elicits voltage-gated, rapidly activating K+-selective currents similar to KCNQ1. However, unlike KCNQ1, KCNQ2 and KCNQ3 currents are not augmented by coexpression with the KCNQ1 beta subunit, KCNE1 (minK, IsK). Northern blot analyses reveal that KCNQ2 and KCNQ3 exhibit similar expression patterns in different regions within the brain. Interestingly, coexpression of KCNQ2 and KCNQ3 results in a substantial synergistic increase in current amplitude. Coexpression of KCNE1 with the two channels strongly suppressed current amplitude and slowed kinetics of activation. The pharmacological and biophysical properties of the K+ currents observed in the coinjected oocytes differ somewhat from those observed after injecting either KCNQ2 or KCNQ3 by itself. The functional interaction between KCNQ2 and KCNQ3 provides a framework for understanding how mutations in either channel can cause a form of idiopathic generalized epilepsy.
良性家族性新生儿惊厥（BFNC）是一类特发性全身性癫痫，是一种常染色体显性遗传的新生儿疾病。BFNC与两个假定的钾通道基因KCNQ2和KCNQ3的突变有关。氨基酸序列比较显示，这两个基因与KvLQT1有很强的同源性，KvLQT1是由KCNQ1编码的钾通道，它导致了超过50%的遗传性长QT综合征。在这里，我们描述了由KCNQ2和KCNQ3 cDNA编码的钾通道的克隆、功能表达和特性。单独地，在非洲爪蟾卵母细胞中表达KCNQ2或KCNQ3会引发电压门控、快速激活的钾选择性电流，类似于KCNQ1。然而，与KCNQ1不同的是，KCNQ2和KCNQ3的电流不会因与KCNQ1β亚基KCNE1（minK，IsK）共表达而增强。Northern印迹分析显示，KCNQ2和KCNQ3在脑内不同区域表现出相似的表达模式。有趣的是，KCNQ2和KCNQ3共表达会导致电流幅度大幅协同增加。KCNE1与这两个通道共表达会强烈抑制电流幅度并减缓激活动力学。在共注射的卵母细胞中观察到的钾电流的药理学和生物物理特性与单独注射KCNQ2或KCNQ3后观察到的特性有所不同。KCNQ2和KCNQ3之间的功能相互作用为理解任一通道中的突变如何导致一种特发性全身性癫痫提供了一个框架。
