Sodium channel selectivity and conduction: Prokaryotes have devised their own molecular strategy

Finol‐Urdaneta, Rocio K.; Wang, Yibo; Al-Sabi, Ahmed; Zhao, Chunfeng; Noskov, Sergei Y.; French, Robert J.

doi:10.1085/jgp.201311037

Cited by 57 publications

(120 citation statements)

References 63 publications

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“…1B) is in a conducting state, allowing for studies of multiple ion movements. We examine the effects of EEEE protonation and reveal extensive protein fluctuations, unseen in previous simulations on shorter timescales (11,(20)(21)(22), but suggested to play a role in a recent study (23). We will demonstrate that protein fluctuations away from the published crystal structure are critical for describing ion conduction mechanisms.…”

mentioning

confidence: 82%

Ion conduction and conformational flexibility of a bacterial voltage-gated sodium channel

Boiteux

Vorobyov

Allen

2014

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

101

199

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Voltage-gated Na + channels play an essential role in electrical signaling in the nervous system and are key pharmacological targets for a range of disorders. The recent solution of X-ray structures for the bacterial channel Na v Ab has provided an opportunity to study functional mechanisms at the atomic level. This channel's selectivity filter exhibits an EEEE ring sequence, characteristic of mammalian Ca 2+ , not Na + , channels. This raises the fundamentally important question: just what makes a Na + channel conduct Na + ions? Here we explore ion permeation on multimicrosecond timescales using the purpose-built Anton supercomputer. We isolate the likely protonation states of the EEEE ring and observe a striking flexibility of the filter that demonstrates the necessity for extended simulations to study conduction in this channel. We construct free energy maps to reveal complex multi-ion conduction via knock-on and "pass-by" mechanisms, involving concerted ion and glutamate side chain movements. Simulations in mixed ionic solutions reveal relative energetics for Na + , K + , and Ca 2+ within the pore that are consistent with the modest selectivity seen experimentally. We have observed conformational changes in the pore domain leading to asymmetrical collapses of the activation gate, similar to proposed inactivated structures of Na v Ab, with helix bending involving conserved residues that are critical for slow inactivation. These structural changes are shown to regulate access to fenestrations suggested to be pathways for lipophilic drugs and provide deeper insight into the molecular mechanisms connecting drug activity and slow inactivation.

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mentioning

confidence: 82%

Ion conduction and conformational flexibility of a bacterial voltage-gated sodium channel

Boiteux

Vorobyov

Allen

2014

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

101

199

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“…Na V Ab/I217C could conceivably also represent an inactivated state; however, extensive studies of slow inactivation of mammalian and bacterial sodium channels by mutagenesis and molecular modeling support the idea that a change in the conformation of the ion selectivity filter to a nonconductive state is a critical part of the slow-inactivation process 4,5 . Since molecular dynamics studies indicate that the ion selectivity filter is in an open conformation in Na V Ab/I217C 6–8 , it is not likely to be in a slow-inactivated state. On the other hand, the structures of Na V Ab wild-type and Na V Rh fit the criteria for slow-inactivated states 2,3 .…”

Section: Pore Openingmentioning

confidence: 99%

The chemical basis for electrical signaling

2017

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“…-binding/permeation, we used multidimensional umbrella sampling methods, a powerful computational technique used with a considerable success in the past for various ion channels (46). Umbrella sampling simulations were performed with harmonic biasing potentials with a force constant of 20 kcal/(mol·Å 2 ) along the z axis.…”

Section: +mentioning

confidence: 99%

Molecular mechanism of Zn ²⁺ inhibition of a voltage-gated proton channel

Qiu

Chamberlin

Watkins

et al. 2016

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

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Voltage-gated proton (Hv1) channels are involved in many physiological processes, such as pH homeostasis and the innate immune response. Zn 2+ is an important physiological inhibitor of Hv1. Sperm cells are quiescent in the male reproductive system due to Zn 2+ inhibition of Hv1 channels, but become active once introduced into the low-Zn 2+ -concentration environment of the female reproductive tract. How Zn 2+ inhibits Hv1 is not completely understood. In this study, we use the voltage clamp fluorometry technique to identify the molecular mechanism of Zn 2+ inhibition of Hv1. We find that Zn 2+ binds to both the activated closed and resting closed states of the Hv1 channel, thereby inhibiting both voltage sensor motion and gate opening. Mutations of some Hv1 residues affect only Zn 2+ inhibition of the voltage sensor motion, whereas mutations of other residues also affect Zn 2+ inhibition of gate opening. These effects are similar in monomeric and dimeric Hv1 channels, suggesting that the Zn 2+ -binding sites are localized within each subunit of the dimeric Hv1. We propose that Zn 2+ binding has two major effects on Hv1: (i) at low concentrations, Zn 2+ binds to one site and prevents the opening conformational change of the pore of Hv1, thereby inhibiting proton conduction; and (ii) at high concentrations, Zn 2+ , in addition, binds to a second site and inhibits the outward movement of the voltage sensor of Hv1. Elucidating the molecular mechanism of how Zn 2+ inhibits Hv1 will further our understanding of Hv1 function and might provide valuable information for future drug development for Hv1 channels.Hv1 | voltage-gated proton channel | Zn2 + | inhibition | molecular model

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Sodium channel selectivity and conduction: Prokaryotes have devised their own molecular strategy

Abstract: The molecular strategy for alkali cation selectivity by a bacterial sodium channel resembles those of eukaryotic calcium and potassium channels, rather than those of eukaryotic sodium channels.

Cited by 57 publications

References 63 publications

Ion conduction and conformational flexibility of a bacterial voltage-gated sodium channel

Ion conduction and conformational flexibility of a bacterial voltage-gated sodium channel

The chemical basis for electrical signaling

Molecular mechanism of Zn ²⁺ inhibition of a voltage-gated proton channel

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Sodium channel selectivity and conduction: Prokaryotes have devised their own molecular strategy

Abstract: The molecular strategy for alkali cation selectivity by a bacterial sodium channel resembles those of eukaryotic calcium and potassium channels, rather than those of eukaryotic sodium channels.

Cited by 57 publications

References 63 publications

Ion conduction and conformational flexibility of a bacterial voltage-gated sodium channel

Ion conduction and conformational flexibility of a bacterial voltage-gated sodium channel

The chemical basis for electrical signaling

Molecular mechanism of Zn 2+ inhibition of a voltage-gated proton channel

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Product

Resources

About

Molecular mechanism of Zn ²⁺ inhibition of a voltage-gated proton channel