Biology subjects

Franciolini, F.

Publications and source records attributed to Franciolini, F..

2 recordsLinked to original sources

bioRxiv2021

Gating current noise produced by Brownian models of a voltage sensor

The activation of voltage-dependent ion channels is associated with the movement gating charges, that give rise to gating currents. Although gating currents originating from a single channel are too small to be detected, analysis of the fluctuations of macroscopic gating currents originating from a population of channels can make a good guess of their magnitude. The analysis of experimental gating current fluctuations, when interpreted in terms of a Markov model of channel activation, are in accordance with the presence of a main step along the activation pathway carrying 2.3-2.4 e0 of charge. To give a physical interpretation to these results and to relate them to the known atomic structure of the voltage sensor domain, we employed a Brownian model of voltage-dependent gating that we recently developed using structural information and applying the laws of electrodynamics. The model was capable to reproduce gating currents and gating current fluctuations essentially similar to those experimentally observed. The detailed study of this model output, also performed by making several simplifications aimed at understanding the basic dependencies of the gating current fluctuations, suggests that in real ion channels the voltage sensor does not move in a fully Markovian regimen due to the relatively low (<5 kT) energy barriers separating successive intermediate states. As a consequence, the simultaneous jump of multiple gating charges through the gating pore becomes frequent, and this occurrence is at the origin of the relatively high single-step charge detected by assuming Markovian behavior.

biophysics↗

bioRxiv2020

Why are voltage gated Na channels faster than K channels: a multi-scale hierarchical model

The generation of action potentials in excitable cells requires different activation kinetics of voltage gated Na (NaV) and K (KV) channels. NaV channels activate much faster and allow the initial Na+ influx that generates the depolarizing phase and propagates the signal. Recent experimental results suggest that the molecular basis for this kinetic difference is an amino acid side chain located in the gating pore of the voltage sensor domain, which is a highly conserved isoleucine in KV channels, but an equally highly conserved threonine in NaV channels. Mutagenesis suggests that the hydrophobicity of this side chain in Shaker KV channels regulates the energetic barrier that gating charges need to overcome to move through the gating pore, and ultimately the rate of channel opening. We use a multi-scale modeling approach to test this hypothesis. We use high resolution molecular dynamics to study the effect of the mutation on polarization charge within the gating pore. We then incorporate these results in a lower resolution model of voltage gating to predict the effect of the mutation on the movement of gating charges. The predictions of our hierarchical model are fully consistent with the tested hypothesis, thus suggesting that the faster activation kinetics of NaV channels comes from a stronger dielectric polarization by threonine (NaV channel) produced as the first gating charge enters the gating pore, compared to isoleucine (KV channel). eTOC SummaryVoltage-gated Na+ channels activate faster than K+ channels in excitable cells. Catacuzzeno et al. develop a model that shows how the dielectric properties of a divergent side-chain produce this difference in speed.

biophysics↗