Which of the following is a voltage-gated sodium channel subunit responsible for sensing membrane potential?
Voltage-gated sodium channels that drive rapid upstroke of action potentials are built from one polypeptide folded into four homologous repeats, each repeat having six transmembrane helices S1 to S6. S1 through S4 cluster peripherally as the voltage-sensing domain, while S5, S6 and the intervening loop dip back into the membrane as P-loop to create the ion conducting pore. The hallmark of voltage sensing resides in S4, which exhibits a repeating pattern Arg-X-X where positively charged arginine or lysine appears every third residue, flanked by hydrophobic side chains. These gating charges sit inside a water-filled crevice stabilized by acidic countercharges in S1 to S3 and a hydrophobic plug. At resting negative interior potential electrostatic attraction holds S4 inward. Depolarization weakens this force, permitting S4 to move outward about 10 to 12 angstroms via a helical screw or sliding helix mechanism, carrying three to four elementary charges across the field. This movement drags the short S4-S5 linker, levering S6 helices apart and opening the intracellular activation gate, allowing sodium influx. S1-S3 and P-loop contribute stabilization and selectivity respectively, but charge translocation and voltage detection originate from S4.
Ref: Alberts et al., Molecular Biology of the Cell, 7th ed., Chapter 11: Voltage-Gated Ion Channels and Electrical Properties of Membranes.