Ion homeostasis is essential for the hearing process. Depolarizing K influx into sensory hair cells through apical mechanosensitive channels requires a high K concentration (150 mM) in the scala media. It is generated by the epithelium of the stria vascularis which needs basolateral Cl channels for the recycling of Cl taken up by NaK2Cl cotransport. These channels are ClC-K/barttin heteromers. Mutations in barttin lead to Bartter syndrome IV, which combines severe renal salt loss with congenital deafness. We have generated a mouse model in which barttin is selectively inactivated in the inner ear, avoiding early lethality due to salt and fluid loss. These mice display congenital deafness. Endocochlear K⁺ concentration was normal, but endocochlear potential was reduced. This sufficed to suppress otoacoustic emissions from outer hair cells. Outer hair cells also degenerated progressively. K leaves outer hair cells (OHCs) through basal KCNQ4 K channels. We have discivered that KCNQ4 mutations lead to slowly progressive hearing loss in humans and have generated appropriate mouse models. After exiting OHCs, K must be removed by supporting Deiter's cells which express the K-Cl cotransporters KCC3 and KCC4. Knock-out of either cotransporter leads to deafness in mice, with KCC3 disruption resulting in a slowly progressing hearing loss that is associated with hair cell degeneration. In addition, KCC4 KO leads to renal tubular acidosis, while the mice lacking KCC3 display severe neurodegeneration similar to patients with Anderman syndrome who also lack KCC3.

References

Kubisch C., Schroeder B.C., Friedrich T., Lütjohann B., El-Amraoui A., Marlin S., Petit C., Jentsch T.J. (1999). KCNQ4, a potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Cell96: 437-446.

Boettger T., Hübner C.A., Maier H., Rust M., Beck F.X., Jentsch T.J. (2002). Deafness and renal tubular acidosis in mice lacking the K-Cl co-transporter KCC4. Nature416, 874-878.

Boettger T., Rust M.B., Maier H., Seidenbecher T., Schweizer M., Keating D., Faulhaber J., Ehmke H., Pfeffer C., Scheel O., Lemcke B., Host J., Leuwer R., Pape H.C., Völkl H., Hübner C.A., Jentsch T.J. (2003). Loss of K-Cl cotransporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold. EMBO J. 22, 5422-5434.

Rickheit G., Maier H., Strenzke N., Andreescu C.E., De Zeeuw C.I., Zdebik A.A., Jentsch T.J. (2008). Endocochlear potential depends on chloride channels: mechanism underlying deafness in Bartter syndrome IV. EMBO J. 27, 2907-2917.