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Multiscale modeling shows that dielectric differences make NaV channels faster than KV channels
Luigi Catacuzzeno1, Luigi Sforna1, Fabio Franciolini1
1Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy.
The Journal of General Physiology
|January 27, 2021
Summary
Voltage-gated sodium (NaV) channels activate faster than potassium (KV) channels due to a threonine residue. This residue enhances dielectric polarization, speeding up NaV channel activation for action potential generation.
Area of Science:
- Molecular Biophysics
- Computational Biology
- Neuroscience
Background:
- Action potential generation in excitable cells relies on distinct activation speeds of voltage-gated sodium (NaV) and potassium (KV) channels.
- NaV channels exhibit faster activation kinetics, crucial for initiating the depolarizing phase of action potentials.
- A conserved amino acid side chain in the voltage sensor domain's gating pore (threonine in NaV, isoleucine in KV) is hypothesized to underlie this kinetic difference.
Purpose of the Study:
- To investigate the molecular basis for the differential activation kinetics between NaV and KV channels.
- To test the hypothesis that the hydrophobicity of the gating pore side chain (threonine vs. isoleucine) influences channel activation rates.
Main Methods:
- Employed a multiscale modeling approach combining high-resolution molecular dynamics and lower-resolution voltage gating models.
- Molecular dynamics simulations were used to assess the impact of amino acid side chain mutations on polarization charge within the gating pore.
- Results from molecular dynamics were integrated into a voltage gating model to predict the effects of mutations on gating charge movement.
Main Results:
- The multiscale modeling predictions strongly supported the hypothesis.
- Threonine in NaV channels induces greater dielectric polarization within the gating pore compared to isoleucine in KV channels.
- This enhanced polarization by threonine accelerates the movement of gating charges, leading to faster NaV channel activation.
Conclusions:
- The difference in activation kinetics between NaV and KV channels is attributed to the distinct dielectric polarization effects of threonine and isoleucine residues.
- Faster NaV channel activation is facilitated by stronger dielectric polarization mediated by threonine as the initial gating charge enters the pore.
- This study provides a mechanistic explanation for the kinetic diversity essential for neuronal signaling.
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