Possible Mechanism of Ion Selectivity in Eukaryotic Voltage-Gated Sodium Channels

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]).

Download Full-text

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

IUPHAR/BPS Guide to Pharmacology CITE ◽

10.2218/gtopdb/f82/2019.4 ◽

2019 ◽

Vol 2019 (4) ◽

Cited By ~ 2

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]).

Download Full-text

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

Entropy ◽

10.3390/e22121390 ◽

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.

Download Full-text