Abstract
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.
Highlights
Voltage-gated sodium channels are essential for electrical signalling across cell membranes, and their opening initiates the action potential in excitable cells
Sodium channels enable the translocation of sodium ions across cell membranes with exquisite selectivity over other types of cations, permitting the specific cascade of events associated with electrical signalling in cells
We have examined the relative permeabilities of different monovalent and divalent cations in NavMs channels expressed in HEK293T cells; these results correlate well with electrostatic calculations of different ion profiles, based on the crystal structure
Summary
Voltage-gated sodium channels are essential for electrical signalling across cell membranes, and their opening initiates the action potential in excitable cells. Sodium channels enable the translocation of sodium ions across cell membranes with exquisite selectivity over other types of cations, permitting the specific cascade of events associated with electrical signalling in cells. Eukaryotic sodium channels (Navs) consist of pore-forming a subunits, which alone are sufficient for functional expression of the channel properties (Noda et al, 1986). They are single polypeptide chains of ~2,000 residues that contain four homologous repeats, each of which comprises a structural domain (designated DI-DIV), where each domain consists of six transmembrane helices, designated S1–S6. The selectivity filter (SF), which determines the channel’s Na+ permeability over other cations, is formed by the close association of the P loops from each of the polypeptide chains
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