Ovsepian Saak V, LeBerre Marie, Steuber Volker, O'Leary Valerie B, Leibold Christian, Oliver Dolly J
Institute of Bio-Medical Imaging at Helmholtz Zentrum Munich, Neuherberg, Germany; International Centre for Neurotherapeutics, Dublin City University, Dublin, Ireland.
National Centre for Biomedical Engineering, National University of Ireland, Galway, Ireland.
Pharmacol Ther. 2016 Mar;159:93-101. doi: 10.1016/j.pharmthera.2016.01.005. Epub 2016 Jan 26.
The diversity of pore-forming subunits of KV1 channels (KV1.1-KV1.8) affords their physiological versatility and predicts a range of functional impairments resulting from genetic aberrations. Curiously, identified so far human neurological conditions associated with dysfunctions of KV1 channels have been linked exclusively to mutations in the KCNA1 gene encoding for the KV1.1 subunit. The absence of phenotypes related to irregularities in other subunits, including the prevalent KV1.2 subunit of neurons is highly perplexing given that deletion of the corresponding kcna2 gene in mouse models precipitates symptoms reminiscent to those of KV1.1 knockouts. Herein, we critically evaluate the molecular and biophysical characteristics of the KV1.1 protein in comparison with others and discuss their role in the greater penetrance of KCNA1 mutations in humans leading to the neurological signs of episodic ataxia type 1 (EA1). Future research and interpretation of emerging data should afford new insights towards a better understanding of the role of KV1.1 in integrative mechanisms of neurons and synaptic functions under normal and disease conditions.
KV1通道（KV1.1 - KV1.8）的成孔亚基的多样性赋予了它们生理功能的多样性，并预示了一系列由基因畸变导致的功能障碍。奇怪的是，迄今为止已确定的与KV1通道功能障碍相关的人类神经疾病仅与编码KV1.1亚基的KCNA1基因突变有关。鉴于在小鼠模型中删除相应的kcna2基因会引发类似于KV1.1基因敲除的症状，那么为何没有发现与其他亚基异常相关的表型，尤其是神经元中普遍存在的KV1.2亚基，这令人深感困惑。在此，我们严格评估了KV1.1蛋白与其他蛋白相比的分子和生物物理特性，并讨论了它们在人类KCNA1突变导致发作性共济失调1型（EA1）神经症状的更高外显率中所起的作用。未来对新出现数据的研究和解读应该能为更好地理解KV1.1在正常和疾病状态下神经元整合机制及突触功能中的作用提供新的见解。
