scholarly journals Changes in Ion Selectivity Following the Asymmetrical Addition of Charge to the Selectivity Filter of Bacterial Sodium Channels

Entropy ◽  
2020 ◽  
Vol 22 (12) ◽  
pp. 1390
Author(s):  
Olena A. Fedorenko ◽  
Igor A. Khovanov ◽  
Stephen K. Roberts ◽  
Carlo Guardiani
Keyword(s):  
Molecular Dynamics ◽  
Sodium Channels ◽  
Ion Selectivity ◽  
Selectivity Filter ◽  
Na Channels ◽  
Site Specific ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Gating Charge ◽  
Dynamics Simulations

Voltage-gated sodium channels (NaVs) play fundamental roles in eukaryotes, but their exceptional size hinders their structural resolution. Bacterial NaVs are simplified homologues of their eukaryotic counterparts, but their use as models of eukaryotic Na+ channels is limited by their homotetrameric structure at odds with the asymmetric Selectivity Filter (SF) of eukaryotic NaVs. This work aims at mimicking the SF of eukaryotic NaVs by engineering radial asymmetry into the SF of bacterial channels. This goal was pursued with two approaches: the co-expression of different monomers of the NaChBac bacterial channel to induce the random assembly of heterotetramers, and the concatenation of four bacterial monomers to form a concatemer that can be targeted by site-specific mutagenesis. Patch-clamp measurements and Molecular Dynamics simulations showed that an additional gating charge in the SF leads to a significant increase in Na+ and a modest increase in the Ca2+ conductance in the NavMs concatemer in agreement with the behavior of the population of random heterotetramers with the highest proportion of channels with charge −5e. We thus showed that charge, despite being important, is not the only determinant of conduction and selectivity, and we created new tools extending the use of bacterial channels as models of eukaryotic counterparts.

Selectivity Filter Residues Contribute Unequally to Pore Stabilization in Voltage-Gated Sodium Channels†

Biochemistry ◽  
2005 ◽  
Vol 44 (42) ◽  
pp. 13874-13882 ◽  
Author(s):  
Karlheinz Hilber ◽  
Walter Sandtner ◽  
Touran Zarrabi ◽  
Eva Zebedin ◽  
Oliver Kudlacek ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Selectivity Filter ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

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

2016 ◽  
Vol 113 (48) ◽  
pp. 13762-13767 ◽  
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.

Modeling ion permeation through a bacterial voltage-gated calcium channel CaVAb using molecular dynamics simulations

2017 ◽  
Vol 13 (1) ◽  
pp. 208-214 ◽  
Author(s):  
Jamal Adiban ◽  
Yousef Jamali ◽  
Hashem Rafii-Tabar
Keyword(s):  
Molecular Dynamics ◽  
Calcium Channels ◽  
Calcium Channel ◽  
Molecular Dynamics Simulations ◽  
Selectivity Filter ◽  
Ion Permeation ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Voltage Gated Calcium Channel ◽  
Dynamics Simulations

Ca2+ion binds tightly to the center of the selectivity filter of voltage-gated calcium channels.

scholarly journals Protonation state of inhibitors determines interaction sites within voltage-gated sodium channels

2018 ◽  
Vol 115 (14) ◽  
pp. E3135-E3144 ◽  
Author(s):  
Amanda Buyan ◽  
Delin Sun ◽  
Ben Corry
Keyword(s):  
Sodium Channel ◽  
Sodium Channels ◽  
The Body ◽  
Voltage Gated ◽  
Interaction Sites ◽  
Voltage Gated Sodium Channels ◽  
Neutral Compounds ◽  
Dynamics Simulations ◽  
A Site ◽  
Subtype Selective

Voltage-gated sodium channels are essential for carrying electrical signals throughout the body, and mutations in these proteins are responsible for a variety of disorders, including epilepsy and pain syndromes. As such, they are the target of a number of drugs used for reducing pain or combatting arrhythmias and seizures. However, these drugs affect all sodium channel subtypes found in the body. Designing compounds to target select sodium channel subtypes will provide a new therapeutic pathway and would maximize treatment efficacy while minimizing side effects. Here, we examine the binding preferences of nine compounds known to be sodium channel pore blockers in molecular dynamics simulations. We use the approach of replica exchange solute tempering (REST) to gain a more complete understanding of the inhibitors’ behavior inside the pore of NavMs, a bacterial sodium channel, and NavPas, a eukaryotic sodium channel. Using these simulations, we are able to show that both charged and neutral compounds partition into the bilayer, but neutral forms more readily cross it. We show that there are two possible binding sites for the compounds: (i) a site on helix 6, which has been previously determined by many experimental and computational studies, and (ii) an additional site, occupied by protonated compounds in which the positively charged part of the drug is attracted into the selectivity filter. Distinguishing distinct binding poses for neutral and charged compounds is essential for understanding the nature of pore block and will aid the design of subtype-selective sodium channel inhibitors.

scholarly journals Voltage-gated sodium channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
William A. Catterall ◽  
Alan L. Goldin ◽  
Stephen G. Waxman
Keyword(s):  
Sodium Channels ◽  
Ion Selectivity ◽  
Structural Features ◽  
Fatty Acyl ◽  
Transmembrane Segment ◽  
Α Subunit ◽  
Voltage Gated ◽  
Transmembrane Segments ◽  
Voltage Gated Sodium Channels ◽  
Acyl Chains

Sodium channels are voltage-gated sodium-selective ion channels present in the membrane of most excitable cells. Sodium channels comprise of one pore-forming α subunit, which may be associated with either one or two β subunits [176]. α-Subunits consist of four homologous domains (I–IV), each containing six transmembrane segments (S1–S6) and a pore-forming loop. The positively charged fourth transmembrane segment (S4) acts as a voltage sensor and is involved in channel gating. The crystal structure of the bacterial NavAb channel has revealed a number of novel structural features compared to earlier potassium channel structures including a short selectivity filter with ion selectivity determined by interactions with glutamate side chains [268]. Interestingly, the pore region is penetrated by fatty acyl chains that extend into the central cavity which may allow the entry of small, hydrophobic pore-blocking drugs [268]. Auxiliary β1, β2, β3 and β4 subunits consist of a large extracellular N-terminal domain, a single transmembrane segment and a shorter cytoplasmic domain.The nomenclature for sodium channels was proposed by Goldin et al., (2000) [143] and approved by the NC-IUPHAR Subcommittee on sodium channels (Catterall et al., 2005, [51]).

scholarly journals Voltage-gated sodium channels (NaV) in GtoPdb v.2021.3

2021 ◽  
Vol 2021 (3) ◽  
Author(s):  
William A. Catterall ◽  
Alan L. Goldin ◽  
Stephen G. Waxman
Keyword(s):  
Sodium Channels ◽  
Ion Selectivity ◽  
Structural Features ◽  
Fatty Acyl ◽  
Transmembrane Segment ◽  
Α Subunit ◽  
Voltage Gated ◽  
Transmembrane Segments ◽  
Voltage Gated Sodium Channels ◽  
Acyl Chains

Sodium channels are voltage-gated sodium-selective ion channels present in the membrane of most excitable cells. Sodium channels comprise of one pore-forming α subunit, which may be associated with either one or two β subunits [177]. α-Subunits consist of four homologous domains (I-IV), each containing six transmembrane segments (S1-S6) and a pore-forming loop. The positively charged fourth transmembrane segment (S4) acts as a voltage sensor and is involved in channel gating. The crystal structure of the bacterial NavAb channel has revealed a number of novel structural features compared to earlier potassium channel structures including a short selectivity filter with ion selectivity determined by interactions with glutamate side chains [274]. Interestingly, the pore region is penetrated by fatty acyl chains that extend into the central cavity which may allow the entry of small, hydrophobic pore-blocking drugs [274]. Auxiliary β1, β2, β3 and β4 subunits consist of a large extracellular N-terminal domain, a single transmembrane segment and a shorter cytoplasmic domain.The nomenclature for sodium channels was proposed by Goldin et al., (2000) [144] and approved by the NC-IUPHAR Subcommittee on sodium channels (Catterall et al., 2005, [52]).

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