Charge-voltage curves of many voltage-gated ion channels exhibit hysteresis but such curves are also a direct measure of free energy of channel gating and, hence, should be path-independent. Here, we identify conditions to measure steady-state charge-voltage curves and show that these are curves are not hysteretic. Charged residues in transmembrane segments of voltage-gated ion channels (VGICs) sense and respond to changes in the electric field. The movement of these gating charges underpins voltage-dependent activation and is also a direct metric of the net free-energy of channel activation. However, for most voltage-gated ion channels, the charge-voltage (Q-V) curves appear to be dependent on initial conditions. For instance, Q-V curves of Shaker potassium channel obtained by hyperpolarizing from 0 mV is left-shifted compared to those obtained by depolarizing from a holding potential of −80 mV. This hysteresis in Q-V curves is a common feature of channels in the VGIC superfamily and raises profound questions about channel energetics because the net free-energy of channel gating is a state function and should be path independent. Due to technical limitations, conventional gating current protocols are limited to test pulse durations of <500 ms, which raises the possibility that the dependence of Q-V on initial conditions reflects a lack of equilibration. Others have suggested that the hysteresis is fundamental thermodynamic property of voltage-gated ion channels and reflects energy dissipation due to measurements under non-equilibrium conditions inherent to rapid voltage jumps (Villalba-Galea. 2017. Channels. https://doi.org/10.1080/19336950.2016.1243190). Using an improved gating current and voltage-clamp fluorometry protocols, we show that the gating hysteresis arising from different initial conditions in Shaker potassium channel is eliminated with ultra-long (18–25 s) test pulses. Our study identifies a modified gating current recording protocol to obtain steady-state Q-V curves of a voltage-gated ion channel. Above all, these findings demonstrate that the gating hysteresis in Shaker channel is a kinetic phenomenon rather than a true thermodynamic property of the channel and the charge-voltage curve is a true measure of the net-free energy of channel gating.
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January 24 2023
Charge-voltage curves of Shaker potassium channel are not hysteretic at steady state
John Cowgill,
1
Departments of Anesthesiology, Neuroscience, Biochemistry and Molecular Biophysics, Center for Investigation of Membrane Excitability Diseases, Washington University School of Medicine
, St. Louis, MO, USA
John Cowgill: john.cowgill@scilifelab.se
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Baron Chanda
1
Departments of Anesthesiology, Neuroscience, Biochemistry and Molecular Biophysics, Center for Investigation of Membrane Excitability Diseases, Washington University School of Medicine
, St. Louis, MO, USA
Correspondence to Baron Chanda: bchanda@wustl.edu
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1
Departments of Anesthesiology, Neuroscience, Biochemistry and Molecular Biophysics, Center for Investigation of Membrane Excitability Diseases, Washington University School of Medicine
, St. Louis, MO, USA
Correspondence to Baron Chanda: bchanda@wustl.edu
John Cowgill: john.cowgill@scilifelab.se
J. Cowgill’s current affiliation is Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden.
This work is part of a special issue on Structure and Function of Ion Channels in Native Cells and Macromolecular Complexes.
Received:
January 26 2021
Revision Received:
February 16 2022
Accepted:
January 03 2023
Online Issn: 1540-7748
Print Issn: 0022-1295
Funding
Funder(s):
National Institutes of Health
- Award Id(s): NS101723,NS081293,NS116850,T32 HL-07936-17
© 2023 Cowgill and Chanda
2023
Cowgill and Chanda
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Gen Physiol (2023) 155 (3): e202112883.
Article history
Received:
January 26 2021
Revision Received:
February 16 2022
Accepted:
January 03 2023
Citation
John Cowgill, Baron Chanda; Charge-voltage curves of Shaker potassium channel are not hysteretic at steady state. J Gen Physiol 6 March 2023; 155 (3): e202112883. doi: https://doi.org/10.1085/jgp.202112883
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