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

Shoichiro Horita, Tomoyuki Ono, Saul Gonzalez-Resines, Yuko Ono, Megumi Yamachi, Songji Zhao, Yuko Maejima, Kenju Shimomura, Carmen Domene

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4 Citations (SciVal)


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 (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.

Original languageEnglish
Article number6668
JournalScientific Reports
Issue number1
Early online date23 Mar 2021
Publication statusPublished - 31 Dec 2021


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