Figure 1. Alignment of S4 sequences for Na_V1.4, Ca_V1.1 and Shaker K⁺ channels.

Positively charged residues are delineated with a shaded background (blue) for the R0 to R7 position. Mutations of these basic residues may produce a gating pore current activated by hyperpolarization (hyperpol), by depolarization (depol), or give rise to a proton transporter (xporter). The gating pore waist lies between R2 and R3, and voltage-dependent translocation of substituted R residues on S4 through this region regulates the flow of gating pore current. HypoPP mutations (red) are clustered at arginines in the R1 or R2 position of Na_V1.4 and Ca_V1.1. Mutations of Na_V1.4 at IV-R1 (green) are associated with PMC, not HypoPP, and do not produce gating pore current. A mixed variant of periodic paralysis is associated with mutations at Na_V1.4 II-R3 (yellow) which causes a depolarization-activated gating pore.