Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295, Japan.
Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
Sci Rep. 2021 Mar 23;11(1):6668. doi: 10.1038/s41598-021-86121-5.
Developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome, the most severe end of neonatal diabetes mellitus, is caused by mutation in the ATP-sensitive potassium (K) channel. In addition to diabetes, DEND patients present muscle weakness as one of the symptoms, and although the muscle weakness is considered to originate in the brain, the pathological effects of mutated K channels in skeletal muscle remain elusive. Here, we describe the local effects of the K channel on muscle by expressing the mutation present in the K channels of the DEND syndrome in the murine skeletal muscle cell line C2C12 in combination with computer simulation. The present study revealed that the DEND mutation can lead to a hyperpolarized state of the muscle cell membrane, and molecular dynamics simulations based on a recently reported high-resolution structure provide an explanation as to why the mutation reduces ATP sensitivity and reveal the changes in the local interactions between ATP molecules and the channel.
发育迟缓、癫痫和新生儿糖尿病（DEND）综合征是新生儿糖尿病中最严重的一种，由三磷酸腺苷（ATP）敏感性钾（K）通道突变引起。除了糖尿病，DEND 患者还表现出肌肉无力作为其中一种症状，尽管肌肉无力被认为起源于大脑，但突变的 K 通道在骨骼肌中的病理作用仍不清楚。在这里，我们通过在鼠骨骼肌细胞系 C2C12 中表达 DEND 综合征 K 通道中的突变，结合计算机模拟，描述 K 通道对肌肉的局部影响。本研究表明，DEND 突变可导致肌细胞膜超极化，基于最近报道的高分辨率结构的分子动力学模拟解释了为什么突变降低了 ATP 敏感性，并揭示了 ATP 分子与通道之间局部相互作用的变化。
