Deletion of the Ca2+-Activated Potassium (BK) α-Subunit but Not the BKβ1-Subunit Leads to Progressive Hearing Loss

The large conductance voltage- and Ca2+-activated potassium (BK) channel has been suggested to play an important role in the signal transduction process of cochlear inner hair cells. BK channels have been shown to be composed of the pore-forming α-subunit coexpressed with the auxiliary β1-subunit. Analyzing the hearing function and cochlear phenotype of BK channel α- ( BKα-/-) and β1-subunit ( BKβ 1-/-) knockout mice, we demonstrate normal hearing function and cochlear structure of BKβ 1-/-mice. During the first 4 postnatal weeks also, BKα-/-mice most surprisingly did not show any obvious hearing deficits. High-frequency hearing loss developed in BKα-/-mice only from ≈8 weeks postnatally onward and was accompanied by a lack of distortion product otoacoustic emissions, suggesting outer hair cell (OHC) dysfunction. Hearing loss was linked to a loss of the KCNQ4 potassium channel in membranes of OHCs in the basal and midbasal cochlear turn, preceding hair cell degeneration and leading to a similar phenotype as elicited by pharmacologic blockade of KCNQ4 channels. Although the actual link between BK gene deletion, loss of KCNQ4 in OHCs, and OHC degeneration requires further investigation, data already suggest human BK-coding s/o1 gene mutation as a susceptibility factor for progressive deafness, similar to KCNQ4 potassium channel mutations.