Differential effect of brief electrical stimulation on voltage-gated potassium channels

Electrical stimulation of neuronal tissue is a promising strategy to treat a variety of neurological disorders. The mechanism of neuronal activation by external electrical stimulation is governed by voltage-gated ion channels. This stimulus, typically brief in nature, leads to membrane potential depolarization, which increases ion flow across the membrane by increasing the open probability of these voltage-gated channels. In spiking neurons, it is activation of voltage-gated sodium channels (NaV channels) that leads to action potential generation. However, several other types of voltage-gated channels are expressed that also respond to electrical stimulation. In this study, we examine the response of voltage-gated potassium channels (KV channels) to brief electrical stimulation by whole cell patch-clamp electrophysiology and computational modeling. We show that nonspiking amacrine neurons of the retina exhibit a large variety of responses to stimulation, driven by different KV-channel subtypes. Computational modeling reveals substantial differences in the response of specific KV-channel subtypes that is dependent on channel kinetics. This suggests that the expression levels of different KV-channel subtypes in retinal neurons are a crucial predictor of the response that can be obtained. These data expand our knowledge of the mechanisms of neuronal activation and suggest that KV-channel expression is an important determinant of the sensitivity of neurons to electrical stimulation. NEW & NOTEWORTHY This paper describes the response of various voltage-gated potassium channels (KV channels) to brief electrical stimulation, such as is applied during prosthetic electrical stimulation. We show that the pattern of response greatly varies between KV channel subtypes depending on activation and inactivation kinetics of each channel. Our data suggest that problems encountered when artificially stimulating neurons such as cessation in firing at high frequencies, or “fading,” may be attributed to KV-channel activation.

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An emerging consensus on voltage-dependent gating from computational modeling and molecular dynamics simulations

The Journal of General Physiology ◽

10.1085/jgp.201210873 ◽

2012 ◽

Vol 140 (6) ◽

pp. 587-594 ◽

Cited By ~ 134

Author(s):

Ernesto Vargas ◽

Vladimir Yarov-Yarovoy ◽

Fatemeh Khalili-Araghi ◽

William A. Catterall ◽

Michael L. Klein ◽

...

Keyword(s):

Molecular Dynamics ◽

Computational Modeling ◽

Md Simulations ◽

Missing Information ◽

Voltage Gated ◽

Voltage Dependent ◽

Voltage Gated Channels ◽

Voltage Gated Ion Channels ◽

Dynamics Simulations ◽

Resolution Structure

Developing an understanding of the mechanism of voltage-gated ion channels in molecular terms requires knowledge of the structure of the active and resting conformations. Although the active-state conformation is known from x-ray structures, an atomic resolution structure of a voltage-dependent ion channel in the resting state is not currently available. This has motivated various efforts at using computational modeling methods and molecular dynamics (MD) simulations to provide the missing information. A comparison of recent computational results reveals an emerging consensus on voltage-dependent gating from computational modeling and MD simulations. This progress is highlighted in the broad context of preexisting work about voltage-gated channels.

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Small and large cutaneous fibers display different excitability properties to slowly increasing ramp pulses

Journal of Neurophysiology ◽

10.1152/jn.00629.2019 ◽

2020 ◽

Vol 124 (3) ◽

pp. 883-894

Author(s):

Jenny Tigerholm ◽

Tatiana Nielson Hoberg ◽

Dorthe Brønnum ◽

Mette Vittinghus ◽

Ken Steffen Frahm ◽

...

Keyword(s):

Ion Channels ◽

Computational Modeling ◽

Nerve Fibers ◽

Perception Threshold ◽

Voltage Gated ◽

Tracking Technique ◽

Threshold Tracking ◽

Electrical Pulses ◽

The Difference ◽

Voltage Gated Ion Channels

When large nerve fibers are stimulated by long, slowly increasing electrical pulses, interactive mechanisms counteract the stimulation, which is called accommodation. The perception threshold tracking technique was able to assess accommodation in both small and large fibers. The novelty of this study is that large fibers displayed accommodation, whereas small fibers did not. Additionally, the difference in accommodation between the fiber could be linked to expression of voltage-gated ion channels by means of computational modeling.

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Fluorine-19 NMR and computational quantification of isoflurane binding to the voltage-gated sodium channel NaChBac

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1609939113 ◽

2016 ◽

Vol 113 (48) ◽

pp. 13762-13767 ◽

Cited By ~ 25

Author(s):

Monica N. Kinde ◽

Vasyl Bondarenko ◽

Daniele Granata ◽

Weiming Bu ◽

Kimberly C. Grasty ◽

...

Keyword(s):

Sodium Channel ◽

Binding Sites ◽

Ion Selectivity ◽

Selectivity Filter ◽

Inactivation Kinetics ◽

Voltage Gated Sodium Channel ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Binding Data ◽

Quantitative Analyses

Voltage-gated sodium channels (NaV) play an important role in general anesthesia. Electrophysiology measurements suggest that volatile anesthetics such as isoflurane inhibit NaVby stabilizing the inactivated state or altering the inactivation kinetics. Recent computational studies suggested the existence of multiple isoflurane binding sites in NaV, but experimental binding data are lacking. Here we use site-directed placement of19F probes in NMR experiments to quantify isoflurane binding to the bacterial voltage-gated sodium channel NaChBac.19F probes were introduced individually to S129 and L150 near the S4–S5 linker, L179 and S208 at the extracellular surface, T189 in the ion selectivity filter, and all phenylalanine residues. Quantitative analyses of19F NMR saturation transfer difference (STD) spectroscopy showed a strong interaction of isoflurane with S129, T189, and S208; relatively weakly with L150; and almost undetectable with L179 and phenylalanine residues. An orientation preference was observed for isoflurane bound to T189 and S208, but not to S129 and L150. We conclude that isoflurane inhibits NaChBac by two distinct mechanisms: (i) as a channel blocker at the base of the selectivity filter, and (ii) as a modulator to restrict the pivot motion at the S4–S5 linker and at a critical hinge that controls the gating and inactivation motion of S6.

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Immobilizing the Moving Parts of Voltage-Gated Ion Channels

The Journal of General Physiology ◽

10.1085/jgp.116.3.461 ◽

2000 ◽

Vol 116 (3) ◽

pp. 461-476 ◽

Cited By ~ 97

Author(s):

Richard Horn ◽

Shinghua Ding ◽

Hermann J. Gruber

Keyword(s):

Ion Channels ◽

Potassium Channels ◽

Sodium Channel ◽

Ultraviolet Irradiation ◽

Voltage Sensors ◽

Voltage Gated ◽

Voltage Gated Ion Channels ◽

S4 Segment ◽

Moving Parts ◽

Gated Ion Channels

Voltage-gated ion channels have at least two classes of moving parts, voltage sensors that respond to changes in the transmembrane potential and gates that create or deny permeant ions access to the conduction pathway. To explore the coupling between voltage sensors and gates, we have systematically immobilized each using a bifunctional photoactivatable cross-linker, benzophenone-4-carboxamidocysteine methanethiosulfonate, that can be tethered to cysteines introduced into the channel protein by mutagenesis. To validate the method, we first tested it on the inactivation gate of the sodium channel. The benzophenone-labeled inactivation gate of the sodium channel can be trapped selectively either in an open or closed state by ultraviolet irradiation at either a hyperpolarized or depolarized voltage, respectively. To verify that ultraviolet light can immobilize S4 segments, we examined its relative effects on ionic and gating currents in Shaker potassium channels, labeled at residue 359 at the extracellular end of the S4 segment. As predicted by the tetrameric stoichiometry of these potassium channels, ultraviolet irradiation reduces ionic current by approximately the fourth power of the gating current reduction, suggesting little cooperativity between the movements of individual S4 segments. Photocross-linking occurs preferably at hyperpolarized voltages after labeling residue 359, suggesting that depolarization moves the benzophenone adduct out of a restricted environment. Immobilization of the S4 segment of the second domain of sodium channels prevents channels from opening. By contrast, photocross-linking the S4 segment of the fourth domain of the sodium channel has effects on both activation and inactivation. Our results indicate that specific voltage sensors of the sodium channel play unique roles in gating, and suggest that movement of one voltage sensor, the S4 segment of domain 4, is at least a two-step process, each step coupled to a different gate.

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Zinc and Copper Influence Excitability of Rat Olfactory Bulb Neurons by Multiple Mechanisms

Journal of Neurophysiology ◽

10.1152/jn.2001.86.4.1652 ◽

2001 ◽

Vol 86 (4) ◽

pp. 1652-1660 ◽

Cited By ~ 65

Author(s):

Michelle S. Horning ◽

Paul Q. Trombley

Keyword(s):

Ion Channels ◽

Potassium Channels ◽

Olfactory Bulb ◽

Membrane Potentials ◽

Repetitive Firing ◽

Delayed Rectifier ◽

Voltage Gated ◽

Voltage Gated Ion Channels ◽

Olfactory Bulb Neurons ◽

Gated Ion Channels

Zinc and copper are highly concentrated in several mammalian brain regions, including the olfactory bulb and hippocampus. Whole cell electrophysiological recordings were made from rat olfactory bulb neurons in primary culture to compare the effects of zinc and copper on synaptic transmission and voltage-gated ion channels. Application of either zinc or copper eliminated GABA-mediated spontaneous inhibitory postsynaptic potentials. However, in contrast to the similarity of their effects on inhibitory transmission, spontaneous glutamate-mediated excitatory synaptic activity was completely blocked by copper but only inhibited by zinc. Among voltage-gated ion channels, zinc or copper inhibited TTX-sensitive sodium channels and delayed rectifier-type potassium channels but did not prevent the firing of evoked single action potentials or dramatically alter their kinetics. Zinc and copper had distinct effects on transient A-type potassium currents. Whereas copper only inhibited the A-type current, zinc modulation of A-type currents resulted in either potentiation or inhibition of the current depending on the membrane potential. The effects of zinc and copper on potassium channels likely underlie their effects on repetitive firing in response to long-duration step depolarizations. Copper reduced repetitive firing independent of the initial membrane voltage. In contrast, whereas zinc reduced repetitive firing at membrane potentials associated with zinc-mediated enhancement of the A-type current (−50 mV), in a significant proportion of neurons, zinc increased repetitive firing at membrane potentials associated with zinc-mediated inhibition of the A-type current (−90 mV). Application of zinc or copper also inhibited voltage-gated Ca2+ channels, suggesting a possible role for presynaptic modulation of neurotransmitter release. Despite similarities between the effects of zinc and copper on some ligand- and voltage-gated ion channels, these data suggest that their net effects likely contribute to differential modulation of neuronal excitability.

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Voltage gating of ion channels

Quarterly Reviews of Biophysics ◽

10.1017/s0033583500002894 ◽

1994 ◽

Vol 27 (1) ◽

pp. 1-40 ◽

Cited By ~ 283

Author(s):

F. J. Sigworth

Keyword(s):

Ion Channels ◽

Action Potential ◽

Sodium Channels ◽

Calcium Ions ◽

Neurotransmitter Release ◽

Voltage Gating ◽

Voltage Gated ◽

Voltage Gated Calcium Channels ◽

Voltage Gated Sodium Channels ◽

Voltage Gated Ion Channels

Voltage-gated ion channels are membrane proteins that play a central role in the propagation and transduction of cellular signals (Hille, 1992). Calcium ions entering cells through voltage-gated calcium channels serve as the trigger for neurotransmitter release, muscle contraction, and the release of hormones. Voltage-gated sodium channels initiate the nerve action potential and provide for its rapid propagation because the ion fluxes through these channels regeneratively cause more channels to open.

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A novel single-domain Na+-selective voltage-gated channel in photosynthetic eukaryotes

10.1101/2020.04.29.068528 ◽

2020 ◽

Author(s):

Katherine E. Helliwell ◽

Abdul Chrachri ◽

Julie Koester ◽

Susan Wharam ◽

Alison R. Taylor ◽

...

Keyword(s):

Single Domain ◽

Inactivation Kinetics ◽

Control Mechanisms ◽

Electrical Excitability ◽

Voltage Gated ◽

Photosynthetic Eukaryotes ◽

Voltage Dependent ◽

Gated Channel ◽

Voltage Gated Channels ◽

Short Time

AbstractThe evolution of Na+-selective four-domain voltage-gated channels (4D-Navs) in animals allowed rapid Na+-dependent electrical excitability, and enabled the development of sophisticated systems for rapid and long-range signalling. Whilst bacteria encode single-domain Na+-selective voltage-gated channels (BacNav), they typically exhibit much slower kinetics than 4D-Navs, and are not thought to have crossed the prokaryote-eukaryote boundary. As such, the capacity for rapid Na+-selective signalling is considered to be confined to certain animal taxa, and absent from photosynthetic eukaryotes. Certainly, in land plants, such as the Venus Flytrap where fast electrical excitability has been described, this is most likely based on fast anion channels. Here, we report a unique class of eukaryotic Na+-selective single-domain channels (EukCatBs) that are present primarily in haptophyte algae, including the ecologically important calcifying coccolithophores. The EukCatB channels exhibit very rapid voltage-dependent activation and inactivation kinetics, and sensitivity to the highly selective 4D-Nav blocker tetrodotoxin. The results demonstrate that the capacity for rapid Na+-based signalling in eukaryotes is not restricted to animals or to the presence of 4D-Navs. The EukCatB channels therefore represent an independent evolution of fast Na+-based electrical signalling in eukaryotes that likely contribute to sophisticated cellular control mechanisms operating on very short time scales in unicellular algae.One Sentence SummaryThe capacity for rapid Na+-based signalling has evolved in ecologically important coccolithophore species via a novel class of voltage-gated Na+ channels, EukCatBs.

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An unconventional conductance is required for pacemaking of nigral dopamine neurons

10.1101/2020.12.16.423073 ◽

2020 ◽

Author(s):

Kevin Jehasse ◽

Laurent Massotte ◽

Sebastian Hartmann ◽

Romain Vitello ◽

Sofian Ringlet ◽

...

Keyword(s):

Substantia Nigra ◽

Sodium Channels ◽

Dopamine Neurons ◽

Substantia Nigra Pars Compacta ◽

Voltage Gated ◽

Molecular Identity ◽

Voltage Gated Sodium Channels ◽

Voltage Dependent ◽

Ionic Mechanisms ◽

Voltage Gated Channels

ABSTRACTAlthough several ionic mechanisms are known to control rate and regularity of the pacemaker in dopamine (DA) neurons from the substantia nigra pars compacta (SNc), a conductance essential for pacing has yet to be defined. Here we provide pharmacological evidence that pacemaking of SNc DA neurons is enabled by an unconventional conductance. We found that 1-(2,4-xylyl)guanidine (XG), an established blocker of gating pore currents in mutant voltage gated sodium channels, selectively stops pacemaking of DA SNc neurons and is without effect on the main pore of their voltage-gated channels. We isolated a voltage-dependent, non-inactivating XG-sensitive current of 20-25 pA which operates in the relevant subthreshold range and is carried by both Na+ and Cl- ions. While the molecular identity of this conductance remains to be determined, we show that this XG-sensitive current is crucial to sustain pacemaking in these neurons.

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