Referenced in: none

Automatically associated channels: Kv7.4

Title: Aminoglycosides inhibit KCNQ4 channels in cochlear outer hair cells via depletion of phosphatidylinositol(4,5)bisphosphate.

Authors: Michael G Leitner, Christian R Halaszovich, Dominik Oliver

Journal, date & volume: Mol. Pharmacol., 2011 Jan , 79, 51-60

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/20935082

Abstract
Aminoglycoside antibiotics (AGs) are severely ototoxic. AGs cause degeneration of outer hair cells (OHCs), leading to profound and irreversible hearing loss. The underlying mechanisms are not fully understood. OHC survival critically depends on a specific K+ conductance (I(K,n)) mediated by KCNQ4 (Kv7.4) channels. Dysfunction or genetic ablation of KCNQ4 results in OHC degeneration and deafness in mouse and humans. As a common hallmark of all KCNQ isoforms, channel activity requires phosphatidylinositol(4,5)bisphosphate [PI(4,5)P₂]. Because AGs are known to reduce PI(4,5)P₂ availability by sequestration, inhibition of KCNQ4 may be involved in the action of AGs on OHCs. Using whole-cell patch-clamp recordings from rat OHCs, we found that intracellularly applied AGs inhibit I(K,n). The inhibition results from PI(4,5)P₂ depletion indicated by fluorescence imaging of cellular PI(4,5)P₂ and the dependence of inhibition on PI(4,5)P₂ availability and on PI(4,5)P₂ affinity of recombinant KCNQ channels. Likewise, extracellularly applied AGs inhibited I(K,n) and caused substantial depolarization of OHCs, after rapid accumulation in OHCs via a hair cell-specific apical entry pathway. The potency for PI(4,5)P₂ sequestration, strength of I(K,n) inhibition, and resulting depolarization correlated with the known ototoxic potential of the different AGs. Thus, the inhibition of I(K,n) via PI(4,5)P₂ depletion and the resulting depolarization may contribute to AG-induced OHC degeneration. The KCNQ channel openers retigabine and zinc pyrithione rescued KCNQ4/I(K,n) activity from AG-induced inhibition. Pharmacological enhancement of KCNQ4 may thus offer a protective strategy against AG-induced ototoxicity and possibly other ototoxic insults.