Abstract
Prestin in the lateral membrane of outer hair cells, is responsible for electromotility (EM) and a corresponding nonlinear capacitance (NLC). Prestin’s voltage sensitivity is influenced by intracellular chloride. A regulator of intracellular chloride is a stretch-sensitive, non-selective conductance within the lateral membrane, GmetL. We determine that prestin itself possesses a stretch-sensitive, non-selective conductance that is largest in the presence of thiocyanate ions. This conductance is independent of the anion transporter mechanism. Prestin has been modeled, based on structural data from related anion transporters (SLC26Dg and UraA), to have a 7 + 7 inverted repeat structure with anion transport initiated by chloride binding at the intracellular cleft. Mutation of residues that bind intracellular chloride, and salicylate treatment which prevents chloride binding, have no effect on thiocyanate conductance. In contrast, other mutations reduce the conductance while preserving NLC. When superimposed on prestin’s structure, the location of these mutations indicates that the ion permeation pathway lies between the core and gate ring of helices, distinct from the transporter pathway. The uncoupled current is reminiscent of an omega current in voltage-gated ion channels. We suggest that prestin itself is the main regulator of intracellular chloride concentration via a route distinct from its transporter pathway.
Highlights
Prestin in the lateral membrane of outer hair cells, is responsible for electromotility (EM) and a corresponding nonlinear capacitance (NLC)
The size of the current correlates with the magnitude of prestin-associated, voltage-dependent non-linear capacitance (NLC), the electrical signature of Outer hair cell (OHC) mechanical activity, indicating that the current is associated with prestin successfully expressed on the surface of the HEK cell (Fig. 1C)
Prestin has evolved to facilitate hearing in mammals by enhancing auditory thresholds by up to 1000 fold, through cochlear amplification[1,2]. Since it is a member of the SLC26 anion transporter family, it is no surprise that anions, intracellular chloride, control many of its biophysical characteristics[16,17,18]
Summary
Prestin in the lateral membrane of outer hair cells, is responsible for electromotility (EM) and a corresponding nonlinear capacitance (NLC). A regulator of intracellular chloride is a stretch-sensitive, non-selective conductance within the lateral membrane, GmetL. We determine that prestin itself possesses a stretch-sensitive, non-selective conductance that is largest in the presence of thiocyanate ions This conductance is independent of the anion transporter mechanism. Recent modeling and experimental data have established that it most likely has a structure similar to the distantly related bacterial uracil transporter UraA11,12, and this is corroborated by the crystal structure of the more closely related bacterial homologue SLC26Dg13 This modeling experiment, that shows prestin with a 7 + 7 inverted repeat structure, supersedes previous models suggesting similarity of the SLC26 family to the ClC bacterial chloride transporter/ion channel family[12,14,15]. In this paper we show that prestin itself has a tension-sensitive, non-selective leakage conductance similar to GmetL that operates independently of its putative transporter pathway
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