scholarly journals Structural Mechanism of Voltage-Dependent Gating in an Isolated Voltage-Sensing Domain

2013 ◽  
Vol 104 (2) ◽  
pp. 196a
Author(s):  
Qufei Li ◽  
Sherry Wanderling ◽  
Marcin Paduch ◽  
David Medovoy ◽  
Carlos Villalba-Galea ◽  
...  
Keyword(s):  
Voltage Sensing ◽  
Structural Mechanism ◽  
Voltage Dependent ◽  
Voltage Sensing Domain

scholarly journals Structural mechanism of voltage-dependent gating in an isolated voltage-sensing domain

2014 ◽  
Vol 21 (3) ◽  
pp. 244-252 ◽  
Author(s):  
Qufei Li ◽  
Sherry Wanderling ◽  
Marcin Paduch ◽  
David Medovoy ◽  
Abhishek Singharoy ◽  
...  
Keyword(s):  
Voltage Sensing ◽  
Structural Mechanism ◽  
Voltage Dependent ◽  
Voltage Sensing Domain

scholarly journals Control of Slc7a5 sensitivity by the voltage-sensing domain of Kv1 channels

2020 ◽  
Author(s):  
Nazlee Sharmin ◽  
Shawn M. Lamothe ◽  
Victoria A. Baronas ◽  
Grace Silver ◽  
Yubin Hao ◽  
...  
Keyword(s):  
Amino Acid ◽  
Ion Channels ◽  
Functional Outcomes ◽  
Accessory Proteins ◽  
Expression Systems ◽  
Voltage Sensing ◽  
Voltage Dependent ◽  
Heterologous Expression Systems ◽  
Underlying Mechanisms ◽  
Voltage Sensing Domain

ABSTRACTMany voltage-dependent ion channels are regulated by accessory proteins, although the underlying mechanisms and consequences are often poorly understood. We recently reported a novel function of the amino acid transporter Slc7a5 as a powerful regulator of Kv1.2 voltage-dependent activation. In this study, we report that Kv1.1 channels are also regulated by Slc7a5, albeit with different functional outcomes. In heterologous expression systems, Kv1.1 exhibits prominent current enhancement (‘disinhibition’) with holding potentials more negative than −120 mV. Disinhibition of Kv1.1 is strongly attenuated by shRNA knockdown of endogenous Slc7a5. We investigated a variety of chimeric combinations of Kv1.1 and Kv1.2, demonstrating that exchange of the voltage-sensing domain controls the sensitivity and response to Slc7a5. Overall, our study highlights additional Slc7a5-sensitive Kv1 subunits, and demonstrates that features of Slc7a5 sensitivity can be swapped by exchanging voltage-sensing domains.IMPACT STATEMENTThe voltage-sensing mechanism of a subfamily of potassium channels can be powerfully modulated in unconventional ways, by poorly understood regulatory partners.

scholarly journals Control of Slc7a5 sensitivity by the voltage-sensing domain of Kv1 channels

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Shawn M Lamothe ◽  
Nazlee Sharmin ◽  
Grace Silver ◽  
Motoyasu Satou ◽  
Yubin Hao ◽  
...  
Keyword(s):  
Functional Outcomes ◽  
Accessory Proteins ◽  
Expression Systems ◽  
Voltage Sensing ◽  
Disinhibition Effect ◽  
Channel Inhibition ◽  
Voltage Dependent ◽  
Specific Position ◽  
Heterologous Expression Systems ◽  
Voltage Sensing Domain

Many voltage-dependent ion channels are regulated by accessory proteins. We recently reported powerful regulation of Kv1.2 potassium channels by the amino acid transporter Slc7a5. In this study, we report that Kv1.1 channels are also regulated by Slc7a5, albeit with different functional outcomes. In heterologous expression systems, Kv1.1 exhibits prominent current enhancement ('disinhibition') with holding potentials more negative than −120 mV. Knockdown of endogenous Slc7a5 leads to larger Kv1.1 currents and strongly attenuates the disinhibition effect, suggesting that Slc7a5 regulation of Kv1.1 involves channel inhibition that can be reversed by supraphysiological hyperpolarizing voltages. We investigated chimeric combinations of Kv1.1 and Kv1.2, demonstrating that exchange of the voltage-sensing domain controls the sensitivity and response to Slc7a5, and localize a specific position in S1 with prominent effects on Slc7a5 sensitivity. Overall, our study highlights multiple Slc7a5-sensitive Kv1 subunits, and identifies the voltage-sensing domain as a determinant of Slc7a5 modulation of Kv1 channels.

scholarly journals Voltage-sensing domain mode shift is coupled to the activation gate by the N-terminal tail of hERG channels

2012 ◽  
Vol 140 (3) ◽  
pp. 293-306 ◽  
Author(s):  
Peter S. Tan ◽  
Matthew D. Perry ◽  
Chai Ann Ng ◽  
Jamie I. Vandenberg ◽  
Adam P. Hill
Keyword(s):  
Physiological Role ◽  
Amphipathic Helix ◽  
Voltage Sensing ◽  
Mode Shift ◽  
Activation Gate ◽  
N Terminus ◽  
Voltage Dependent ◽  
Flow Through ◽  
Voltage Sensing Domain ◽  
Herg Channels

Human ether-a-go-go–related gene (hERG) potassium channels exhibit unique gating kinetics characterized by unusually slow activation and deactivation. The N terminus of the channel, which contains an amphipathic helix and an unstructured tail, has been shown to be involved in regulation of this slow deactivation. However, the mechanism of how this occurs and the connection between voltage-sensing domain (VSD) return and closing of the gate are unclear. To examine this relationship, we have used voltage-clamp fluorometry to simultaneously measure VSD motion and gate closure in N-terminally truncated constructs. We report that mode shifting of the hERG VSD results in a corresponding shift in the voltage-dependent equilibrium of channel closing and that at negative potentials, coupling of the mode-shifted VSD to the gate defines the rate of channel closure. Deletion of the first 25 aa from the N terminus of hERG does not alter mode shifting of the VSD but uncouples the shift from closure of the cytoplasmic gate. Based on these observations, we propose the N-terminal tail as an adaptor that couples voltage sensor return to gate closure to define slow deactivation gating in hERG channels. Furthermore, because the mode shift occurs on a time scale relevant to the cardiac action potential, we suggest a physiological role for this phenomenon in maximizing current flow through hERG channels during repolarization.

scholarly journals The HCN domain couples voltage gating and cAMP response in hyperpolarization-activated cyclic nucleotide-gated channels

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Alessandro Porro ◽  
Andrea Saponaro ◽  
Federica Gasparri ◽  
Daniel Bauer ◽  
Christine Gross ◽  
...  
Keyword(s):  
Cyclic Nucleotide ◽  
Channel Gating ◽  
Hcn Channels ◽  
Structural Mechanism ◽  
Cyclic Nucleotide Gated Channels ◽  
Channel Opening ◽  
Mode Of Operation ◽  
Voltage Dependent ◽  
Upward Displacement ◽  
Voltage Sensing Domain

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control spontaneous electrical activity in heart and brain. Binding of cAMP to the cyclic nucleotide-binding domain (CNBD) facilitates channel opening by relieving a tonic inhibition exerted by the CNBD. Despite high resolution structures of the HCN1 channel in the cAMP bound and unbound states, the structural mechanism coupling ligand binding to channel gating is unknown. Here we show that the recently identified helical HCN-domain (HCND) mechanically couples the CNBD and channel voltage sensing domain (VSD), possibly acting as a sliding crank that converts the planar rotational movement of the CNBD into a rotational upward displacement of the VSD. This mode of operation and its impact on channel gating are confirmed by computational and experimental data showing that disruption of critical contacts between the three domains affects cAMP- and voltage-dependent gating in three HCN isoforms.

New Molecular Scaffolds for Fluorescent Voltage Indicators

2018 ◽  
Author(s):  
Steven Boggess ◽  
Shivaani Gandhi ◽  
Brian Siemons ◽  
Nathaniel Huebsch ◽  
Kevin Healy ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Action Potentials ◽  
Induced Pluripotent Stem Cell ◽  
Molecular Wire ◽  
Voltage Sensing ◽  
Design Synthesis ◽  
Cardiac Action ◽  
Action Potential Waveform ◽  
Induced Pluripotent ◽  
Voltage Sensing Domain

<div> <p>The ability to non-invasively monitor membrane potential dynamics in excitable cells like neurons and cardiomyocytes promises to revolutionize our understanding of the physiology and pathology of the brain and heart. Here, we report the design, synthesis, and application of a new class of fluorescent voltage indicator that makes use of a fluorene-based molecular wire as a voltage sensing domain to provide fast and sensitive measurements of membrane potential in both mammalian neurons and human-derived cardiomyocytes. We show that the best of the new probes, fluorene VoltageFluor 2 (fVF 2) readily reports on action potentials in mammalian neurons, detects perturbations to cardiac action potential waveform in human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes, shows a substantial decrease in phototoxicity compared to existing molecular wire-based indicators, and can monitor cardiac action potentials for extended periods of time. Together, our results demonstrate the generalizability of a molecular wire approach to voltage sensing and highlights the utility of fVF 2 for interrogating membrane potential dynamics.</p> </div>

Quantum Calculation of Proton and Other Charge Transfer Steps in Voltage Sensing in the Kv1.2 Channel

2019 ◽  
Author(s):  
Alisher M Kariev ◽  
Michael Green
Keyword(s):  
Charge Transfer ◽  
Energy Charge ◽  
Quantum Calculation ◽  
Quantum Calculations ◽  
Gating Current ◽  
Transmembrane Segment ◽  
Voltage Sensing ◽  
Standard Models ◽  
Charge Displacement ◽  
Voltage Sensing Domain

Quantum calculations on 976 atoms of the voltage sensing domain of the K<sub>v</sub>1.2 channel, with protons in several positions, give energy, charge transfer, and other properties. Motion of the S4 transmembrane segment that accounts for gating current in standard models is shown not to occur; there is H<sup>+ </sup>transfer instead. The potential at which two proton positions cross in energy approximately corresponds to the gating potential for the channel. The charge displacement seems approximately correct for the gating current. Two mutations are accounted for (Y266F, R300cit, cit =citrulline). The primary conclusion is that voltage sensing depends on H<sup>+</sup> transfer, not motion of arginine charges.

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