The Mechanism of Na+/K+ Selectivity in Mammalian Voltage-Gated Sodium Channels Based on Molecular Dynamics Simulation

Xia, Mengdie; Liu, Huihui; Li, Yang; Yan, Nieng; Gong, H.

doi:10.1016/j.bpj.2013.04.035

Cited by 42 publications

(65 citation statements)

References 54 publications

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“…As expected, the WT and DEAA mutant allow both Na + and K + ions to quickly permeate into the SF (Fig B in S1 File), consistent with the weak Na + /K + selectivity of these channels reported in our previous works [28, 45]. …”

Section: Resultssupporting

confidence: 91%

Lysine and the Na+/K+ Selectivity in Mammalian Voltage-Gated Sodium Channels

Liu

Xia

et al. 2016

PLoS ONE

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Voltage-gated sodium (Nav) channels are critical in the generation and transmission of neuronal signals in mammals. The crystal structures of several prokaryotic Nav channels determined in recent years inspire the mechanistic studies on their selection upon the permeable cations (especially between Na+ and K+ ions), a property that is proposed to be mainly determined by residues in the selectivity filter. However, the mechanism of cation selection in mammalian Nav channels lacks direct explanation at atomic level due to the difference in amino acid sequences between mammalian and prokaryotic Nav homologues, especially at the constriction site where the DEKA motif has been identified to determine the Na+/K+ selectivity in mammalian Nav channels but is completely absent in the prokaryotic counterparts. Among the DEKA residues, Lys is of the most importance since its mutation to Arg abolishes the Na+/K+ selectivity. In this work, we modeled the pore domain of mammalian Nav channels by mutating the four residues at the constriction site of a prokaryotic Nav channel (NavRh) to DEKA, and then mechanistically investigated the contribution of Lys in cation selection using molecular dynamics simulations. The DERA mutant was generated as a comparison to understand the loss of ion selectivity caused by the K-to-R mutation. Simulations and free energy calculations on the mutants indicate that Lys facilitates Na+/K+ selection by electrostatically repelling the cation to a highly Na+-selective location sandwiched by the carboxylate groups of Asp and Glu at the constriction site. In contrast, the electrostatic repulsion is substantially weakened when Lys is mutated to Arg, because of two intrinsic properties of the Arg side chain: the planar geometric design and the sparse charge distribution of the guanidine group.

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Section: Resultssupporting

confidence: 91%

Lysine and the Na+/K+ Selectivity in Mammalian Voltage-Gated Sodium Channels

Liu

Xia

et al. 2016

PLoS ONE

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“… 52 , 53 Each of these two SFs plays a distinct role in facilitating ion permeation. 54 , 55 The outer SF (EEDD ring) encompasses four amino acid residues, namely E375 (DI), E901 (DII), D1423 (DIII), and D1714 (DIV). These residues ( Figure 1D ) are spread across the four domains.…”

Section: Resultsmentioning

confidence: 99%

“… 63 Furthermore, Xia et al reported that the long side chain of the K residue of VGSC adopts a few distinct conformational states, from which only specific states can allow the passage of sodium. 54 These states were grouped into two main categories; the “on-states” where sodium is allowed to permeate and the “off-states” where the pore is blocked by the side chain of K residues. Xia, moreover, showed that, in the “off-states”, the side chain of K1419 interacts with the facing carboxylate group of E898 from the DEKA filter and the backbone/side chain oxygens of S1710 – one of the pore lining residues.…”

Section: Resultsmentioning

confidence: 99%

Modeling the human Na<sub>v</sub>1.5 sodium channel: structural and mechanistic insights of ion permeation and drug blockade

Ahmed

Hasani

Houghton³

et al. 2017

DDDT

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Abnormalities in the human Nav1.5 (hNav1.5) voltage-gated sodium ion channel (VGSC) are associated with a wide range of cardiac problems and diseases in humans. Current structural models of hNav1.5 are still far from complete and, consequently, their ability to study atomistic interactions of this channel is very limited. Here, we report a comprehensive atomistic model of the hNav1.5 ion channel, constructed using homology modeling technique and refined through long molecular dynamics simulations (680 ns) in the lipid membrane bilayer. Our model was comprehensively validated by using reported mutagenesis data, comparisons with previous models, and binding to a panel of known hNav1.5 blockers. The relatively long classical MD simulation was sufficient to observe a natural sodium permeation event across the channel’s selectivity filters to reach the channel’s central cavity, together with the identification of a unique role of the lysine residue. Electrostatic potential calculations revealed the existence of two potential binding sites for the sodium ion at the outer selectivity filters. To obtain further mechanistic insight into the permeation event from the central cavity to the intracellular region of the channel, we further employed “state-of-the-art” steered molecular dynamics (SMD) simulations. Our SMD simulations revealed two different pathways through which a sodium ion can be expelled from the channel. Further, the SMD simulations identified the key residues that are likely to control these processes. Finally, we discuss the potential binding modes of a panel of known hNav1.5 blockers to our structural model of hNav1.5. We believe that the data presented here will enhance our understanding of the structure–property relationships of the hNav1.5 ion channel and the underlying molecular mechanisms in sodium ion permeation and drug interactions. The results presented here could be useful for designing safer drugs that do not block the hNav1.5 channel.

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“…The resolution of the first such structure (3.5 Å), however, was too low to determine the details of the sites of the ions in the SF, whilst the latter structures contained channel blocker ligands which interfered with ion binding. The sodium ion binding site locations and mechanisms for ion selectivity have also been predicted by a number of molecular dynamics (MD) studies, although they differ considerably in their details (Amaral et al , 2012; Chakrabarti et al , 2013; Stock et al , 2013; Ulmschneider et al , 2013; Xia et al , 2013; Zhang et al , 2013; Boiteux et al , 2014; Furini et al , 2014). …”

Section: Introductionmentioning

confidence: 99%

Molecular basis of ion permeability in a voltage‐gated sodium channel

et al. 2016

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Voltage‐gated sodium channels are essential for electrical signalling across cell membranes. They exhibit strong selectivities for sodium ions over other cations, enabling the finely tuned cascade of events associated with action potentials. This paper describes the ion permeability characteristics and the crystal structure of a prokaryotic sodium channel, showing for the first time the detailed locations of sodium ions in the selectivity filter of a sodium channel. Electrostatic calculations based on the structure are consistent with the relative cation permeability ratios (Na+ ≈ Li+ ≫ K+, Ca2+, Mg2+) measured for these channels. In an E178D selectivity filter mutant constructed to have altered ion selectivities, the sodium ion binding site nearest the extracellular side is missing. Unlike potassium ions in potassium channels, the sodium ions in these channels appear to be hydrated and are associated with side chains of the selectivity filter residues, rather than polypeptide backbones.

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The Mechanism of Na+/K+ Selectivity in Mammalian Voltage-Gated Sodium Channels Based on Molecular Dynamics Simulation

Cited by 42 publications

References 54 publications

Lysine and the Na+/K+ Selectivity in Mammalian Voltage-Gated Sodium Channels

Lysine and the Na+/K+ Selectivity in Mammalian Voltage-Gated Sodium Channels

Modeling the human Na<sub>v</sub>1.5 sodium channel: structural and mechanistic insights of ion permeation and drug blockade

Molecular basis of ion permeability in a voltage‐gated sodium channel

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