Why voltage-gated Ca2+ and bacterial Na+ channels with the same EEEE motif in their selectivity filters confer opposite metal selectivity

Voltage-gated sodium (Na(v)) and calcium (Ca(v)) channels, which play essential biological roles, are characterized by their ability to discriminate the "native" ion from other competing cations. Surprisingly, Na(+)-selective bacterial Na(v) and high voltage-activated Ca(2+)-selective Ca(v) channels both exhibit selectivity filters (the narrowest part of the open pore) lined by four Glu residues that interact specifically with the permeating ions. This raises the intriguing question why selectivity filters with the same EEEE motif are Na(+)-selective in Na(v) channels but Ca(2+)-selective in Ca(v) channels. We show that the different degree of metal hydration inside the pore, which is related to the pore size and rigidity, can account for the opposite ion selectivity in Na(v) and Ca(v) channels with identical EEEE selectivity filters. The results are consistent with experimental estimates of the metal hydration structure in Na(v) and Ca(v) channels with the EEEE motif. They suggest that the protein matrix, which can enhance or attenuate ion-protein interactions relative to ion-solvent interactions by controlling the pore's solvent accessibility, size/rigidity, and charge state, is a key determinant of Ca(2+)vs. Na(+) selectivity in EEEE selectivity filters.