Molecular Properties and Pathophysiological Relevance of the Predominant K+ Conductance in Cochlear Outer Hair Cells

Cochlear outer hair cells (OHCs) are characterised by the voltage-dependent K+ conductance IK,n that previously was shown to be mediated by KCNQ4 (Kv7) channel subunits. IK,n/KCNQ4 dominates the electrical properties of the OHC cell membrane and furthermore is essential for OHC survival. Genetic deletion of KCNQ4 causes progressive degeneration of OHCs and deafness. Similarly, KCNQ4 loss-of-function mutations cause the progressive form of hereditary deafness DFNA2. The molecular mechanism leading to OHC degeneration remains elusive, but the survival of OHCs has been linked directly to KCNQ4 channel function. Strikingly, the loss of OHCs is phenotypically similar to OHC degeneration caused by ototoxic substances and noise damage (acquired hearing loss), but a role of IK,n/KCNQ4 in acquired hearing loss has never been investigated so far. In the present study I investigated the pathophysiological relevance of IK,n for OHC degeneration caused by aminoglycoside (AG) antibiotics. Since KCNQ4 channel function is essential for OHC survival, chemical current augmentation may provide a protective strategy against KCNQ4-related hearing loss. Thus, I analysed whether chemical KCNQ channel openers rescued IK,n currents from pathological inhibition. In brief, I found that AGs rapidly entered OHCs and that entry was necessary for IK,n current inhibition. The inhibition was caused by functional depletion of phospholipids by the AGs that are essential for the function of IK,n/KCNQ4. Various AGs exhibit different ototoxic potential, i.e. neomycin causes OHC degeneration whereas gentamicin damages vestibular hair cells. Strikingly, the degree of IK,n inhibition (neomycin > gentamicin) correlated with the phospholipid binding efficiency and with the ototoxic potential of the respective AG. Given the dependence of OHCs on IK,n, the ototoxic potential of AGs thus may be determined by their chemical nature and by their inhibitory impact on IK,n. Furthermore, I showed that IK,n was sensitive to current augmentation by chemical KCNQ channel openers. A combination of openers rescued IK,n from AG-induced inhibition to wild-type levels indicating full restoration of IK,n activity. Most DFNA2 patients are heterozygous carriers of KCNQ4 mutations that reduce IK,n through a dominant-negative effect. This reduction of IK,n activity causes OHC degeneration. Residual currents in the dominant-negative situation were essentially rescued to wild-type levels by the application of KCNQ channel openers, at least in a heterologous expression system. The current rescue indicated that KCNQ channel openers might be used to stabilise IK,n in heterozygous DFNA2 patients. In summary, the present work demonstrated for the first time a role of the essential OHC K+ conductance IK,n in acquired hearing loss. The dependence of OHCs on IK,n may explain the high vulnerability of OHCs towards ototoxic influences. IK,n current augmentation by chemical KCNQ openers may be used to stabilise IK,n in OHCs and protect the sensory cells from KCNQ4-related degeneration. KCNQ openers rescued IK,n from AG-induced inhibition in OHCs and recombinant KCNQ4 from dominant-negative inhibition by mutant subunits. However, it remains elusive whether chemical KCNQ agonists alleviate OHC degeneration and protect from hearing loss.