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Alkanols inhibit voltage-gated K+ channels via a distinct gating modifying mechanism that prevents gate opening
Alkanols inhibit voltage-gated K+ channels via a distinct gating modifying mechanism that prevents gate opening
- Source :
- SCIENTIFIC REPORTS, Scientific Reports, Scientific reports
- Publication Year :
- 2015
- Publisher :
- Nature Publishing Group, 2015.
-
Abstract
- Alkanols are small aliphatic compounds that inhibit voltage-gated K+ (Kv) channels through a yet unresolved gating mechanism. Kv channels detect changes in the membrane potential with their voltage-sensing domains (VSDs) that reorient and generate a transient gating current. Both 1-Butanol (1-BuOH) and 1-Hexanol (1-HeOH) inhibited the ionic currents of the Shaker Kv channel in a concentration dependent manner with an IC50 value of approximately 50 mM and 3 mM, respectively. Using the non-conducting Shaker-W434F mutant, we found that both alkanols immobilized approximately 10% of the gating charge and accelerated the deactivating gating currents simultaneously with ionic current inhibition. Thus, alkanols prevent the final VSD movement(s) that is associated with channel gate opening. Applying 1-BuOH and 1-HeOH to the Shaker-P475A mutant, in which the final gating transition is isolated from earlier VSD movements, strengthened that neither alkanol affected the early VSD movements. Drug competition experiments showed that alkanols do not share the binding site of 4-aminopyridine, a drug that exerts a similar effect at the gating current level. Thus, alkanols inhibit Shaker-type Kv channels via a unique gating modifying mechanism that stabilizes the channel in its non-conducting activated state.
- Subjects :
- KV CHANNELS
ION-CHANNEL
Plasma protein binding
Gating
Article
Cell Line
Membrane Potentials
MOLECULAR-BASIS
Potassium Channel Blockers
medicine
Medicine and Health Sciences
Animals
Humans
Protein Interaction Domains and Motifs
Shaker
CHARGE MOVEMENT
Binding site
Biology
V CHANNEL
Ion channel
Membrane potential
POLYUNSATURATED FATTY-ACIDS
Binding Sites
Multidisciplinary
Chemistry
Biology and Life Sciences
Potassium channel blocker
Potassium channel
Kinetics
ACTIVATION PATHWAY
GENERAL-ANESTHETICS
Potassium Channels, Voltage-Gated
Alcohols
S4-S5 LINKER
Mutation
Shaker Superfamily of Potassium Channels
Biophysics
POTASSIUM CHANNEL
Human medicine
Hexanols
Engineering sciences. Technology
Ion Channel Gating
Protein Binding
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 20452322
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....47a23a9e01e776ebd572322dc1148684
- Full Text :
- https://doi.org/10.1038/srep17402