Ion Selectivity Strategies of Sodium Channel Selectivity Filters

ConspectusSodium ion channels selectively transport Na⁺ cations across the cell membrane. These integral parts of the cell machinery are implicated in regulating the cardiac, skeletal and smooth muscle contraction, nerve impulses, salt and water homeostasis, as well as pain and taste perception. Their malfunction often results in various channelopathies of the heart, brain, skeletal muscles, and lung; thus, sodium channels are key drug targets for various disorders including cardiac arrhythmias, heart attack, stroke, migraine, epilepsy, pain, cancer, and autoimmune disorders. The ability of sodium channels to discriminate the native Na⁺ among other competing ions in the surrounding fluids is crucial for proper cellular functions. The selectivity filter (SF), the narrowest part of the channel’s open pore, lined with amino acid residues that specifically interact with the permeating ion, plays a major role in determining Na⁺ selectivity. Different sodium channels have different SFs, which vary in the symmetry, number, charge, arrangement, and chemical type of the metal-ligating groups and pore size: epithelial/degenerin/acid-sensing ion channels have generally trimeric SFs lined with three conserved neutral serines and/or backbone carbonyls; eukaryotic sodium channels have EKEE, EEKE, DKEA, and DEKA SFs with an invariant positively charged lysine from the second or third domain; and bacterial voltage-gated sodium (Na_v) channels exhibit symmetrical EEEE SFs, reminiscent of eukaryotic voltage-gated calcium channels. How do these different sodium channel SFs achieve high selectivity for Na⁺ over its key rivals, K⁺ and Ca²⁺? What factors govern the metal competition in these SFs and which of these factors are exploited to achieve Na⁺ selectivity in the different sodium channel SFs? The free energies for replacing K⁺ or Ca²⁺ bound inside different model SFs with Na⁺, evaluated by a combination of density functional theory and continuum dielectric calculations, have shed light on these questions. The SFs of epithelial and eukaryotic Na_v channels select Na⁺ by providing an optimal number and ligating strength of metal ligands as well as a rigid pore whose size fits the cognate Na⁺ ideally. On the other hand, the SFs of bacterial Na_v channels select Na⁺, as the protein matrix attenuates ion–protein interactions relative to ion–solvent interactions by enlarging the pore and allowing water to enter, so the ion interacts indirectly with the conserved glutamates via bridging water molecules. This shows how these various SFs have adapted to the specific physicochemical properties of the native ion, using different strategies to select Na⁺ among its contenders