Which segment of a voltage-gated ion channel detects changes in membrane potential?
Ion channel gating requires conversion of electrical signal into conformational change, accomplished by specialized sensor modules. Voltage-gated channels share a conserved architecture of four domains each comprising six membrane helices. S1, S2 and S3 are largely hydrophobic with interspersed acidic residues forming a charge transfer center and hydrophilic vestibules enabling helix motion. S4 stands out because it contains four to seven positively charged arginine or lysine residues spaced every third position in motif Arg-X-X-Arg, creating a linear array of gating charges along one face of the helix. At rest interior negative potential exerts strong inward electrostatic force on these charges, stabilizing S4 in down position. Membrane depolarization reduces net field, allowing S4 to translate outward and rotate about 10 angstroms, moving three to four charges outward measurable as gating currents before ionic currents appear. The S4-S5 linker connects movement to S6 gate, bending S6 at a conserved glycine to open pore. S5 and S6 together with P-loop provide conduction path but lack repeated basic residues. Hence S4 uniquely detects membrane potential shifts.
Ref: Lodish et al., Molecular Cell Biology, 9th ed., Chapter: Voltage-Sensing Domain S4 Movement and Gating Currents.