The outer vestibule of the Na+ channel-toxin receptor and modulator of permeation as well as gating

Abstract

The outer vestibule of voltage-gated Na(+) channels is formed by extracellular loops connecting the S5 and S6 segments of all four domains ("P-loops"), which fold back into the membrane. Classically, this structure has been implicated in the control of ion permeation and in toxin blockage. However, conformational changes of the outer vestibule may also result in alterations in gating, as suggested by several P-loop mutations that gave rise to gating changes. Moreover, partial pore block by mutated toxins may reverse gating changes induced by mutations. Therefore, toxins that bind to the outer vestibule can be used to modulate channel gating.

Keywords: outer vestibule; rate-dependent block; saxitoxin; sodium channel; tetrodotoxin; use-dependent block.

Figure 1

Transmembrane-folding diagram of the α-subunit of the voltage-gated Na⁺ channel. Probable α-helical segments and polypeptide chains are represented as cylinders and bold lines, respectively. The bold lines represent polypeptide chains. S4 segments (blue) are the voltage sensors.

Figure 2

The gating changes presented in Table 1 are indicated in the Lipkind Fozzard model of the outer vestibule of the voltage-gated Na⁺ channel [92]. Shown are the P-loops of all four domains (DI-DIV). In panels A. and C. all amino acid side chains are depicted. In panels B. and D. only the side chains of amino acid positions for which gating changes are reported in Table 1 are shown. A. and B. present changes in activation, C. and D. show changes in inactivation. The color code corresponds to Table 1.