FIGURE 2.

Structural comparisons between (A) symmetrical, 1 × 6 TM (TM = transmembrane) homotetrameric, bacterial Na channels consisting of four repeat subunit (B) asymmetrical, eukaryotic four domain calcium and sodium channels consisting of 24 transmembrane segments (4 × 6 TM). Each of the four sodium and calcium channel domains consist of a voltage-sensor domain of four transmembrane segments, S1–S4 (blue), akin to voltage sensor only protein (e.g., HVCN1) and a pore domain, S5–S6 (orange), resembling the size of the two membrane segments of the inward rectifying K channels (e.g., KcsA). A dramatic difference between the 1 × 6 TM bacterial sodium channels and 4 × 6 TM calcium and sodium channels are the larger sizes of extracellular turrets rising before the pore selectivity filter, especially L5_I and L5_III which range from 40 to 105 amino acids long. The longest extracellular turret in Domain IV in 4 × 6 TM channels is always the extracellular turret rising after the pore selectivity filter (L6_IV), while L5_IV (the extracellular loop just before the pore selectivity filter) is always short. Comparatively speaking, 1 × 6 TM channels all possess short extracellular turrets of 10–15 amino acids long. Eight core, conserved cysteines populate the L5_I - L5_II - L5_III - L6_IV extracellular turrets in a 4-0-2-2 configuration in all eukaryotic 4 × 6 TM channels. Also novel are singleton N- and C-termini, and cytoplasmic linkers, of which the III-IV linker is almost always 53–57 amino acids long in eukaryotic 4 × 6 TM channels.