SLC26A5 Protein, Human (HEK293)

SLC26A5 is a voltage-sensitive motor protein that drives outer hair cell (OHC) electromotility (eM) and participates in sound amplification in the hearing organ (By similarity). It converts changes in the transmembrane electric potential into mechanical displacements, coupling its expansion to the movement of a charged voltage sensor across the lipid membrane (By similarity). The nature of the voltage sensor remains unclear, with two competing models. In the first model, it acts as an incomplete transporter where intracellular chloride anions serve as extrinsic voltage sensors, driving protein conformational changes sufficient to alter OHC length (By similarity). The second model proposes that multiple charged amino acid residues distributed at membrane interfaces form an intrinsic voltage sensor, generating nonlinear capacitance (NLC) (PubMed:34390643). However, the effective sensor may be a hybrid of intrinsic (charged residues) and extrinsic (bound anions) charges (By similarity). Notably, anion binding partially neutralizes intrinsic positive charges, leaving residual charge as the voltage sensor that shifts from a down (expanded) to an up (contracted) conformation upon depolarization, accompanied by eccentric contraction of the protein's cross-sectional area and increased hydrophobic thickness, leading to membrane thickening and cell contraction (PubMed:34390643). The anion-binding pocket transitions from an inward-open (down) state to an occluded (up) state upon anion binding (PubMed:34390643). Salicylate competitively inhibits voltage-sensor movement by displacing Cl(-) and blocking structural transitions to the contracted state (PubMed:34390643). Additionally, it weakly functions as a Cl(-)/HCO3(-) antiporter, regulating OHC intracellular pH, though initially found incapable of electrogenic anion transport (By similarity). It also supports cardiac mechanical amplification by enhancing actomyosin-based sarcomere contraction (By similarity).