Recovery of KCNQ4 channel function in deafness autosomal dominant locus 2 (DFNA2)-associated deafness using synthetic channel openers

Mrinalini Dey, Murray Edwards College, New Hall, University of Cambridge, Cambridge CB3 0DF

DFNA2 is a hereditary hearing disorder, arising from loss-of-function mutations in the voltage-gated potassium channel KCNQ4. This channel regulates K+ conductance (IK,N) of the outer hair cells (OHCs) in the organ of Corti, which undergo degeneration if there is loss of KCNQ4 function. The result is progressive hearing loss, sometimes resulting in severe deafness by the age of 70. Research published by Leitner et al. (1) in the British Journal of Pharmacology suggests that chemical channel openers may be able to stabilise and recover K+ conductance mediated by KCNQ4. This would prevent OHC degeneration, protecting against DFNA2-associated hearing loss.

Leitner et al. investigated the effect of synthetic channel openers on wild-type KCNQ4 and DFNA2-causing mutants, performing whole cell patch clamp recordings on OHCs. It was found that a combination of zinc-pyrithione and retigabine (ZnP/Ret) was able to restore channel function to the DFNA2-causing mutation most effectively, especially when the DFNA2 mutation was in the proximal C-terminus; channels with mutations in the pore region were completely unresponsive. A similar (but less-pronounced) effect was observed in native IK,N in rat OHCs. Where wild-type and KCNQ4 mutants (of any type) were co-expressed, causing extreme dominant-negative suppression of currents, channel openers restored currents to levels seen in wild-type cells. This is thought to be due to strong activation of the small proportion of homomeric wild-type channels.

This study shows a possible method of recovering channel activity in mutant KCNQ4 using channel openers. Most DFNA2 patients have a heterozygous genotype, causing dominant-negative suppression of channel function. Therefore, restoration of function by chemical channel openers may potentially be useful in stabilising KCNQ conductance and conferring protection against OHC degeneration and hearing loss. Regardless of the particular mutation, this appears to be a promising therapeutic option for many DFNA2 patients.


1. Leitner MG, Feuer A, Ebers O, Schreiber D, Halaszovich CR, Oliver D. Restoration of ion channel function in deafness-causing KCNQ4 mutants by synthetic channel openers. British Journal of Pharmacology 2012; 165: 2244–2259.
doi: 10.1111/j.1476-5381.2011.01697.x

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