Figure 6. Mechanism of Nav channel... | Rockefeller University Press

Figure 6.

$Figure 6. Mechanism of Nav channel block. (A–C) Examples of ion distribution in the toxin-free channel (A) and in the presence of the wild-type GIIIA (B) and GIIIA R13A mutant (C). (D) Proposed schemes of ion permeation in toxin-free channel and complete or incomplete channel block by toxins. Side chains of acidic and basic residues are shown by small red and blue rectangles, respectively. The DEKA locus is at the bottom and the outer carboxylates are at the upper level. Incoming Na+ ions first bind to the outer carboxylates and then to the DEKA locus. TTX binds between the DEKA locus and the outer carboxylates, thus sterically blocking the ion permeation. Conotoxins (CTX) bind superficially and block permeation by occupying ion-binding sites at the outer carboxylates. KIIIA and some GIIIA and PIIIA mutants leave one of the outer carboxylates free, thus producing only a partial block. (E) Plots of ion distribution along the pore axis. For the toxin-free model and for the R13A mutants of GIIIA, which produce incomplete block, there are many ions in the outer pore region with clear maxima at the levels of −12 Å and −7 Å where the ions are attracted to the outer carboxylates. In contrast, for GIIIA, which produces a complete block, the plot has two maxima in the selectivity filter region and near the extracellular entrance to the outer pore, which are separated by a nonpopulated region around −8 Å. (F) Correlation between the residual current value (fraction of single channel current relative to the current through nonblocked channel) and the number of ions at the level of outer carboxylate ring (z = −8 Å) for ion distributions shown in E.$

Mechanism of Nav channel block. (A–C) Examples of ion distribution in the toxin-free channel (A) and in the presence of the wild-type GIIIA (B) and GIIIA R13A mutant (C). (D) Proposed schemes of ion permeation in toxin-free channel and complete or incomplete channel block by toxins. Side chains of acidic and basic residues are shown by small red and blue rectangles, respectively. The DEKA locus is at the bottom and the outer carboxylates are at the upper level. Incoming Na⁺ ions first bind to the outer carboxylates and then to the DEKA locus. TTX binds between the DEKA locus and the outer carboxylates, thus sterically blocking the ion permeation. Conotoxins (CTX) bind superficially and block permeation by occupying ion-binding sites at the outer carboxylates. KIIIA and some GIIIA and PIIIA mutants leave one of the outer carboxylates free, thus producing only a partial block. (E) Plots of ion distribution along the pore axis. For the toxin-free model and for the R13A mutants of GIIIA, which produce incomplete block, there are many ions in the outer pore region with clear maxima at the levels of −12 Å and −7 Å where the ions are attracted to the outer carboxylates. In contrast, for GIIIA, which produces a complete block, the plot has two maxima in the selectivity filter region and near the extracellular entrance to the outer pore, which are separated by a nonpopulated region around −8 Å. (F) Correlation between the residual current value (fraction of single channel current relative to the current through nonblocked channel) and the number of ions at the level of outer carboxylate ring (z = −8 Å) for ion distributions shown in E.