Modelling the activation, opening, inactivation and reopening of the voltage–gated sodium channel

Keynes, R. D.; Elinder, Fredrik

doi:10.1098/rspb.1998.0291

Cited by 30 publications

(46 citation statements)

References 39 publications

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“…At least three elementary charges per VSD must traverse outwards through the membrane electric field to open a channel that corresponds to a considerable displacement of the S4 helix ( Fig. 1A) (2)(3)(4). The positive charges in S4 make salt bridges with negative countercharges on their move through the VSD (4)(5)(6)(7)(8).…”

mentioning

confidence: 99%

“…1A) (2)(3)(4). The positive charges in S4 make salt bridges with negative countercharges on their move through the VSD (4)(5)(6)(7)(8). It has even been proposed that the VSD undergoes a conformational alteration following the opening, when the channel relaxes to an inactivated, that is closed, state (9).…”

mentioning

confidence: 99%

“…Our knowledge about the VSD gating processes, including inactivation, is limited. There is strong experimental data suggesting each voltage sensor (in particular the S4 helix) must adopt at least one intermediate state between the conducting and the resting state (3,4,21), which makes the pathway particularly interesting.…”

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confidence: 99%

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Tracking a complete voltage-sensor cycle with metal-ion bridges

Henrion

Renhorn

Börjesson

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

138

239

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Voltage-gated ion channels open and close in response to changes in membrane potential, thereby enabling electrical signaling in excitable cells. The voltage sensitivity is conferred through four voltage-sensor domains (VSDs) where positively charged residues in the fourth transmembrane segment (S4) sense the potential. While an open state is known from the Kv1.2/2.1 X-ray structure, the conformational changes underlying voltage sensing have not been resolved. We present 20 additional interactions in one open and four different closed conformations based on metal-ion bridges between all four segments of the VSD in the voltage-gated Shaker K channel. A subset of the experimental constraints was used to generate Rosetta models of the conformations that were subjected to molecular simulation and tested against the remaining constraints. This achieves a detailed model of intermediate conformations during VSD gating. The results provide molecular insight into the transition, suggesting that S4 slides at least 12 Å along its axis to open the channel with a 3 10 helix region present that moves in sequence in S4 in order to occupy the same position in space opposite F290 from open through the three first closed states. V oltage-gated ion channels are critical for biological signaling, and they are able to regulate ion flux on a millisecond time scale. To sense changes in membrane voltage, each ion channel is equipped with four voltage-sensor domains (VSDs) connected to a central ion-conducting pore domain. The fourth transmembrane segment (S4) of each VSD carries several positively charged amino-acid residues responsible for VSD gating (1). At least three elementary charges per VSD must traverse outwards through the membrane electric field to open a channel that corresponds to a considerable displacement of the S4 helix ( Fig. 1A) (2-4). The positive charges in S4 make salt bridges with negative countercharges on their move through the VSD (4-8). It has even been proposed that the VSD undergoes a conformational alteration following the opening, when the channel relaxes to an inactivated, that is closed, state (9). In addition to conferring voltage dependence to ion channels, VSDs also regulate enzymes (10), act as voltage-gated proton channels (11,12), are susceptible to disease-causing mutations (13,14), and serve as targets for drugs and toxins (1,(15)(16)(17)(18). Therefore, it is of crucial interest to understand the details underlying voltage sensing by VSDs.Few, if any, segments of membrane proteins have received more attention than the S4 helix of voltage sensors. In addition to their paramount biological importance, they can help us understand fundamental biophysical problems such as why some membrane protein segments can be hydrophilic (19), how charges effectively move through a membrane, or how a potential triggers structural changes on a microsecond time scale. These questions are inherently linked to transient conformations and contacts that can be difficult to capture in a single structure. Although active...

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Tracking a complete voltage-sensor cycle with metal-ion bridges

Henrion

Renhorn

Börjesson

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

138

239

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“…The reason that trapping S4 in domain IV in a resting state slows inactivation is that outward movement of this S4 plays a critical role for fast inactivation [89,[136][137][138]. A similar mechanism is suggested for the site-6 δ-conotoxins that interact with the S4 segment of domain IV close to site 3.…”

Section: Toxinsmentioning

confidence: 89%

“…In Na channels about 12 charges are transferred [77,86], and in Ca channels about 9 charges are transferred [87]. All these studies together suggest that It is generally agreed on that the activation can be divided in two main components: i) independent outward movements of the four S4 helices, followed by ii) a concerted opening step when probably all S4s move together [88][89][90][91][92]. However, the exact movement of S4 and its relation to the other helices in the VSD is still highly debated.…”

Section: Gating Charges Cross the Membrane Electric Field -A Dynamic mentioning

confidence: 94%

Structure, Function, and Modification of the Voltage Sensor in Voltage-Gated Ion Channels

Börjesson

Elinder

2008

Cell Biochem Biophys

122

146

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Voltage-gated ion channels are crucial for both neuronal and cardiac excitability. Decades of research have begun to unravel the intriguing machinery behind voltage sensitivity. Although the details regarding the arrangement and movement in the voltage-sensing domain are still debated, consensus is slowly emerging. There are three competing conceptual models: the helical-screw, the transporter, and the paddle model. In this review we explore the structure of the activated voltage-sensing domain based on the recent X-ray structure of a chimera between Kv1.2 and Kv2.1. We also present a model for the closed state. From this we conclude that upon depolarization the voltage sensor S4 moves ~13 Å outwards and rotates ~180º, thus consistent with the helical-screw model. S4 also moves relative to S3b which is not consistent with the paddle model. One interesting feature of the voltage sensor is that it partially faces the lipid bilayer and therefore can interact both with the membrane itself and with physiological and pharmacological molecules reaching the channel from the membrane.This type of channel modulation is discussed together with other mechanisms for how voltage-sensitivity is modified. Small effects on voltage-sensitivity can have profound effects on excitability. Therefore, medical drugs designed to alter the voltage dependence offer an interesting way to regulate excitability.3

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Advances in Material‐Assisted Electromagnetic Neural Stimulation

Sun,

Xiao,

Chen

et al. 2024

Advanced Materials

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Bioelectricity plays a crucial role in organisms, being closely connected to neural activity and physiological processes. Disruptions in the nervous system can lead to chaotic ionic currents at the injured site, causing disturbances in the local cellular microenvironment, impairing biological pathways, and resulting in a loss of neural functions. Electromagnetic stimulation has the ability to generate internal currents, which can be utilized to counter tissue damage and aid in the restoration of movement in paralyzed limbs. By incorporating implanted materials, electromagnetic stimulation can be targeted more accurately, thereby significantly improving the effectiveness and safety of such interventions. Currently, there have been significant advancements in the development of numerous promising electromagnetic stimulation strategies with diverse materials. This review provides a comprehensive summary of the fundamental theories, neural stimulation modulating materials, material application strategies, and pre‐clinical therapeutic effects associated with electromagnetic stimulation for neural repair. It offers a thorough analysis of current techniques that employ materials to enhance electromagnetic stimulation, as well as potential therapeutic strategies for future applications.This article is protected by copyright. All rights reserved

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Modelling the activation, opening, inactivation and reopening of the voltage–gated sodium channel

Cited by 30 publications

References 39 publications

Tracking a complete voltage-sensor cycle with metal-ion bridges

Tracking a complete voltage-sensor cycle with metal-ion bridges

Structure, Function, and Modification of the Voltage Sensor in Voltage-Gated Ion Channels

Advances in Material‐Assisted Electromagnetic Neural Stimulation

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