Structure based analysis of KATP channel with a DEND syndrome mutation in murine skeletal muscle

Journal article

AbstractDevelopmental delay, epilepsy, and neonatal diabetes (DEND) syndrome, the most severe end of neonatal diabetes mellitus, is caused by mutation in the ATP-sensitive potassium (KATP) 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 KATP channels in skeletal muscle remain elusive. Here, we describe the local effects of the KATP channel on muscle by expressing the mutation present in the KATP 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.

Authors: Horita, S; Ono, T; Gonzalez-Resines, S; Ono, Y; Yamachi, M

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Scientific Reports
• Volume: 11
• Issue: 1
• Pages: 6668-6668
• Article number: 6668
• Publication date: 2021-03-23
• DOI: 10.1038/s41598-021-86121-5
• EISSN: 2045-2322
• ISSN: 2045-2322
• Language: English
• Keywords: Gene; Pathological; Endocrinology; Genetics; Neuroscience; Muscle weakness; Skeletal muscle; Medicine; Potassium channel; Mutation; Internal medicine; Biology