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Published on: June 2, 2023
Structure, function, and modification of the voltage sensor in voltage-gated ion channels
Sara I Börjesson1, Fredrik Elinder
1Department of Clinical and Experimental Medicine, Division of Cell Biology, Linköping University, SE-581 85, Linköping, Sweden.
Voltage-gated ion channels are key to excitability. New models suggest the S4 voltage sensor moves outward and rotates upon depolarization, supporting the helical-screw model and offering insights into channel modulation for therapeutic applications.
Area of Science:
- Biophysics
- Molecular Biology
- Neuroscience
Background:
- Voltage-gated ion channels are essential for cellular electrical signaling in neurons and the heart.
- Understanding the voltage-sensing mechanism is critical for explaining cellular excitability.
- Existing models for voltage-sensor movement, including helical-screw, transporter, and paddle models, are debated.
Purpose of the Study:
- To review the structure of the activated voltage-sensor domain.
- To present a model for the closed state of the voltage-sensor domain.
- To elucidate the movement of the S4 segment during channel activation.
Main Methods:
- Analysis of recent X-ray structures of Kv1.2-Kv2.1 chimera.
- Development of a structural model for the closed state.
- Comparison of observed movements with existing mechanistic models.
Main Results:
- The S4 segment moves approximately 13 Å outwards and rotates approximately 180 degrees upon depolarization.
- Observed S4 movement is consistent with the helical-screw model.
- S4 movement relative to S3b contradicts the paddle model.
- The voltage sensor interacts with the lipid bilayer, suggesting membrane-based modulation.
Conclusions:
- The helical-screw model accurately describes voltage-sensor activation.
- Voltage-sensitivity modulation via membrane interactions offers therapeutic potential.
- Altering voltage dependence is a viable strategy for regulating cellular excitability.
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