Co-assembly of KCNQ4 (Kv7.4) and Erg (Kv11) potassium channels as molecular basis of the characteristic outer hair cell current IK,n

哺乳动物非凡的听觉敏锐度主要依赖于通过外毛细胞体细胞长度的超快变化来主动放大耳蜗。由于这些长度变化是由膜电位变化驱动的，因此灵敏度直接依赖于超快声音诱导的受体电位。在外毛细胞中，钾离子（K+）电流IK，n的独特电压依赖性促进了这种电位变化。因此，IK，n的不寻常特征是耳蜗放大的生物物理先决条件。KCNQ4 (Kv7.4) K+通道亚基已被确定为IK，n的分子组分，但KCNQ4的单一贡献并不能解释天然电流的性质。可能，KCNQ4的未知相互作用伙伴在外毛细胞中产生IK，n。我们提出了一项基于靶向候选方法的研究项目，以阐明IK，n的分子成分。我们确定了IK的kcnq4非典型特征n，这些特征与电压依赖性Erg (Kv11) K+通道的独特家族高度相似。Erg亚基在外毛细胞中与KCNQ4紧密共定位，并令人惊讶地共同组装成相同的离子通道复合物。因此，我们假设Erg亚基与KCNQ4的相互作用决定了IK，n的特殊性质。我们提出了一个工作程序来测试KCNQ4和Erg通道亚基的这种潜在相互作用。最终，我们将使用尖端的遗传技术产生Erg蛋白敲除小鼠，以阐明Erg通道在耳蜗信号处理中的功能重要性。

The extraordinary acuity of mammalian hearing critically depends on active cochlear amplification through ultrafast somatic length changes of outer hair cells. Because these length changes are driven by membrane potential variations, sensitivity directly relies on ultrafast sound-induced receptor potentials. In outer hair cells, such potential changes are facilitated by the unique voltage-dependence of the potassium (K+) current IK,n. Thus, the unusual characteristics of IK,n are a biophysical prerequisite for cochlear amplification. KCNQ4 (Kv7.4) K+ channel subunits have been identified as molecular components of IK,n, but sole contribution of KCNQ4 does not explain the properties of the native current. Probably, yet unknown interaction partners of KCNQ4 produce IK,n in outer hair cells. We present a research project based on a targeted candidate approach to elucidate the molecular constituents of IK,n. We identified KCNQ4-atypical features of IK,n that were highly reminiscent of the distinct family of voltage-dependent Erg (Kv11) K+ channels. Erg subunits colocalised closely with KCNQ4 in outer hair cells and surprisingly co-assembled into the same ion channel complex. Accordingly, we hypothesise that interaction of Erg subunits with KCNQ4 determines the extraordinary properties of IK,n. We propose a working programme to test this potential interaction of KCNQ4 and Erg channel subunits. Ultimately, using cutting-edge genetic techniques we will generate Erg protein knock-out mice to elucidate functional importance of Erg channels for signal processing in the cochlea.