FIGURE 3.

Entry pathways of LAs with different chemical properties. Diagram of the movements of differently charged LA molecules (B, basic amine, N, neutral LA, Q, quaternary charged LA) to and from the channel. Black dashed lines are transitions requiring open activation and fast inactivation gates, as the drug enters from the intracellular side. Black solid lines are transitions probably not strongly depending on the gating state. Violet and blue lines indicate two pathways observed in MD studies for lidocaine and benzocaine, respectively, (Boiteux et al., 2014; Nguyen et al., 2019), where the LA does not pass through the membrane phase but enters a lipophilic pathway within the channel protein towards the side fenestrations (see also Figure 4). Subscript characters represent membrane phase (m), receptor site (r), extracellular (o) and intracellular (i) space. The figure is based on the diagram reported in (Hille, 1977).