| RRC ID |
56203
|
| 著者 |
Nam YW, Baskoylu SN, Gazgalis D, Orfali R, Cui M, Hart AC, Zhang M.
|
| タイトル |
A V-to-F substitution in SK2 channels causes Ca2+ hypersensitivity and improves locomotion in a C. elegans ALS model.
|
| ジャーナル |
Sci Rep
|
| Abstract |
Small-conductance Ca2+-activated K+ (SK) channels mediate medium afterhyperpolarization in the neurons and play a key role in the regulation of neuronal excitability. SK channels are potential drug targets for ataxia and Amyotrophic Lateral Sclerosis (ALS). SK channels are activated exclusively by the Ca2+-bound calmodulin. Previously, we identified an intrinsically disordered fragment that is essential for the mechanical coupling between Ca2+/calmodulin binding and channel opening. Here, we report that substitution of a valine to phenylalanine (V407F) in the intrinsically disordered fragment caused a ~6 fold increase in the Ca2+ sensitivity of SK2-a channels. This substitution resulted in a novel interaction between the ectopic phenylalanine and M411, which stabilized PIP2-interacting residue K405, and subsequently enhanced Ca2+ sensitivity. Also, equivalent valine to phenylalanine substitutions in SK1 or SK3 channels conferred Ca2+ hypersensitivity. An equivalent phenylalanine substitution in the Caenorhabditis elegans (C. elegans) SK2 ortholog kcnl-2 partially rescued locomotion defects in an existing C. elegans ALS model, in which human SOD1G85R is expressed at high levels in neurons, confirming that this phenylalanine substitution impacts channel function in vivo. This work for the first time provides a critical reagent for future studies: an SK channel that is hypersensitive to Ca2+ with increased activity in vivo.
|
| 巻・号 |
8(1)
|
| ページ |
10749
|
| 公開日 |
2018-7-16
|
| DOI |
10.1038/s41598-018-28783-2
|
| PII |
10.1038/s41598-018-28783-2
|
| PMID |
30013223
|
| PMC |
PMC6048120
|
| MeSH |
Amyotrophic Lateral Sclerosis / genetics*
Amyotrophic Lateral Sclerosis / pathology
Animals
Animals, Genetically Modified
Caenorhabditis elegans
Calcium / metabolism*
Calmodulin / metabolism
Cells, Cultured
Disease Models, Animal
Humans
Intrinsically Disordered Proteins / genetics*
Intrinsically Disordered Proteins / metabolism
Locomotion / genetics*
Membrane Potentials / genetics
Neurons / metabolism
Phenylalanine / genetics
Small-Conductance Calcium-Activated Potassium Channels / genetics*
Small-Conductance Calcium-Activated Potassium Channels / metabolism
Superoxide Dismutase-1 / genetics
Superoxide Dismutase-1 / metabolism
Valine / genetics
|
| IF |
4.011
|
| 引用数 |
2
|
| リソース情報 |
| 線虫 |
tm776 |
