LRRC8A Regulates Outer Hair Cell Volume and Electromotility and is Required for Hearing

Damage to the cochlear outer hair cell (OHC) is a major cause of deafness in mammals. OHCs amplify the auditory signals to enhance the sensitivity and sound frequency selectivity of the auditory system. However, detailed mechanisms underlying functional OHC regulation remain unclear. Here, it is demonstrated that volume-regulated anion channels (VRACs) are essential for OHC function. VRAC subunits are highly expressed in OHCs. Genetic deletion of leucin-rich repeat containing 8A (LRRC8A), the obligatory VRAC subunit, in hair cells results in hearing loss, whereas re-expressing LRRC8A in the cochlea restores hearing in LRRC8A-deficient mice. By employing patch-clamp electrophysiology, it is shown that VRAC in OHCs is activated by hypotonicity and is involved in regulating cell volume. Furthermore, the nonlinear capacitance (NLC), a measure of electromotility, is decreased in the OHCs from LRRC8A-deficient mice. Therefore, LRRC8A deficiency compromises electromotility of OHCs and impairs signal amplification. In conclusion, the findings highlight the essential role of VRAC in OHC electromotility and its necessity for auditory function.