Prestin’s fast motor kinetics is essential for mammalian cochlear amplification

Abstract

Prestin (SLC26A5)-mediated voltage-driven elongations and contractions of sensory outer hair cells within the organ of Corti are essential for mammalian cochlear amplification. However, whether this electromotile activity directly contributes on a cycle-by-cycle basis is currently controversial. By restoring motor kinetics in a mouse model expressing a slowed prestin missense variant, this study provides experimental evidence acknowledging the importance of fast motor action to mammalian cochlear amplification. Our results also demonstrate that the point mutation in prestin disrupting anion transport in other proteins of the SLC26 family does not alter cochlear function, suggesting that the potential weak anion transport of prestin is not essential in the mammalian cochlea.

The pathogenic roles of the p.R130S prestin variant in DFNB61 hearing loss

“…Given the recessive nature of DFNB61-associated prestin variants and premature OHC loss found in prestin-KO mice, it is likely that loss-of-function underlies degeneration of OHCs expressing p.R130S prestin. The partially impaired membrane targeting of p.R130S prestin reported previously Takahashi et al, 2023), and further confirmed in this study, is in line with such a loss-of-function-based pathology. Since prestin belongs to the SLC26 anion transport family, it was speculated that OHC loss found in prestin-KO mice might be ascribed to the loss of prestin-mediated anion transport activity (Liberman et al, 2002).…”

“…Although OHC loss was minimal at weaning, by 6 weeks of age OHC loss was evident in cochleae from Slc26a5 R130S/− (Fig. 5) and exceeded that reported in Slc26a5 R130S/R130S (Takahashi et al, 2023).…”

“…2B). Based on our recent study (Takahashi et al, 2023), the NLC pk and C lin values of Slc26a5 R130S/− were smaller than in Slc26a5 R130S/R130S homozygotes. Comparisons between Slc26a5 R130S/− and Slc26a5 R130S/R130S are as follows: NLC pk : 1.3 ± 0.4 pF (mean ± SD, n = 28) vs. 3.2 ± 0.7 pF (mean ± SD, n = 94), P < 0.0001; C lin : 4.7 ± 0.5 pF (mean ± SD, n = 28) vs. 5.4 ± 0.5 pF (mean ± SD, n = 94), P < 0.0001), indicating reduced expression of p.R130S prestin in the lateral membrane of OHCs in Slc26a5 R130S/− compound heterozygotes.…”

“…Hence, we speculate that larger DPOAEs in Slc26a5 R130S/− mice at or before weaning may relate to the relatively higher chloride concentrations in immature OHCs (Takahashi et al, 2023). Taken together, the progressive and frequency-dependent DPOAE threshold shifts found in Slc26a5 R130S/− mice reaffirm the pathogenicity of p.R130S prestin, consistent with its role in slowing prestin's motor activity as demonstrated in our recent study (Takahashi et al, 2023). It is intriguing that DPOAE thresholds were similar for Slc26a5 R130S/− compound heterozygotes and Slc26a5 R130S/R130S homozygotes despite the fact that p.R130S prestin expression is lower in Slc26a5 R130S/− compared to Slc26a5 R130S/R130S (based on the magnitudes of NLC, see above).…”

“…p.R130S prestin, though not truncated, may not fully contribute to OHC maintenance, because its motor function and membrane targeting are impaired Takahashi et al, 2023). In fact, cytocochleograms of Slc26a5 R130S/R130S homozygous mice showed signs of OHC loss at high frequencies at 6 weeks of age (Takahashi et al, 2023).…”