Fig. 3. Non-conserved amino acid substitutions occur in a number or regions of the Na⁺ channel involved in inactivation of the Na⁺ current. Mormyr, mormyrid; Gymnot, gymnotiform. (A) Schematic illustration of the Na⁺ channel. (B) S4–S5 linker in domain II; (C) S4–S5 linker in domain III; (D,E) different parts of the inactivation `ball' or hinged lid in the loop between domains III and IV. Amino acid sequences below the dashed line were used in the PAML analysis. Those above were not used in the analysis but are shown for reference. Red letters are non-conservative amino acid substitutions. Triangles represent amino acid sites at which mutations in human Na⁺ channels cause diseases. The asterisk represents a site at which there are amino acid changes in gymnotiform fish and at which a mutation in humans is related to a disease. Reproduced with permission (Zakon et al., 2006).