Fig. 1.
Protonation state and binding sites of sodium channel pore blockers. Many use-dependent drugs have a pKa near 7.0; therefore, they exist in solution in equilibrium between charged (blue) and neutral (green) states. The neutral form crosses the lipid bilayer more easily than the charged one; thus, it is the species that likely reaches the channel pore through the fenestrations. Buyan et al. (17) find that inside the pore, the neutral and charged species bind in different locations. In particular, the charged form binds the selectivity filter, thereby hindering diffusion of ions to the central cavity.