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Structure based analysis of K ATP channel with a DEND syndrome mutation in murine skeletal muscle.
- Source :
-
Scientific reports [Sci Rep] 2021 Mar 23; Vol. 11 (1), pp. 6668. Date of Electronic Publication: 2021 Mar 23. - Publication Year :
- 2021
-
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 <subscript>ATP</subscript> ) 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 <subscript>ATP</subscript> channels in skeletal muscle remain elusive. Here, we describe the local effects of the K <subscript>ATP</subscript> channel on muscle by expressing the mutation present in the K <subscript>ATP</subscript> 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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 11
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 33758250
- Full Text :
- https://doi.org/10.1038/s41598-021-86121-5