1. Structure based analysis of K ATP channel with a DEND syndrome mutation in murine skeletal muscle.
- Author
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Horita S, Ono T, Gonzalez-Resines S, Ono Y, Yamachi M, Zhao S, Domene C, Maejima Y, and Shimomura K
- Subjects
- Adenosine Triphosphate chemistry, Adenosine Triphosphate metabolism, Animals, Binding Sites, Calcium metabolism, Gene Expression, Glucose metabolism, KATP Channels metabolism, Membrane Potentials, Mice, Molecular Docking Simulation, Molecular Dynamics Simulation, Muscle Development, Muscle Fibers, Skeletal, Potassium Channels, Inwardly Rectifying chemistry, Potassium Channels, Inwardly Rectifying genetics, Potassium Channels, Inwardly Rectifying metabolism, Protein Binding, Protein Conformation, Structure-Activity Relationship, Diabetes Mellitus genetics, Epilepsy genetics, Infant, Newborn, Diseases genetics, KATP Channels chemistry, KATP Channels genetics, Muscle, Skeletal metabolism, Mutation, Psychomotor Disorders genetics
- Abstract
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
ATP ) 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.- Published
- 2021
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