Restoration of Ion Channel Function in Deafness-Causing KCNQ4 Mutants by Synthetic Channel Openers

Br J Pharmacol. 2012 Apr;165(7):2244-59. doi: 10.1111/j.1476-5381.2011.01697.x.


Background and purpose: DFNA2 is a frequent hereditary hearing disorder caused by loss-of-function mutations in the voltage-gated potassium channel KCNQ4 (Kv7.4). KCNQ4 mediates the predominant K(+) conductance, I(K,n) , of auditory outer hair cells (OHCs), and loss of KCNQ4 function leads to degeneration of OHCs resulting in progressive hearing loss. Here we explore the possible recovery of channel activity of mutant KCNQ4 induced by synthetic KCNQ channel openers.

Experimental approach: Whole cell patch clamp recordings were performed on CHO cells transiently expressing KCNQ4 wild-type (wt) and DFNA2-relevant mutants, and from acutely isolated OHCs.

Key results: Various known KCNQ channel openers robustly enhanced KCNQ4 currents. The strongest potentiation was observed with a combination of zinc pyrithione plus retigabine. A similar albeit less pronounced current enhancement was observed with native I(K,n) currents in rat OHCs. DFNA2 mutations located in the channel's pore region abolished channel function and these mutant channels were completely unresponsive to channel openers. However, the function of a DFNA2 mutation located in the proximal C-terminus was restored by the combined application of both openers. Co-expression of wt and KCNQ4 pore mutants suppressed currents to barely detectable levels. In this dominant-negative situation, channel openers essentially restored currents back to wt levels, most probably through strong activation of only the small fraction of homomeric wt channels.

Conclusions and implications: Our data suggest that by stabilizing the KCNQ4-mediated conductance in OHCs, chemical channel openers can protect against OHC degeneration and progression of hearing loss in DFNA2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Carbamates / pharmacology
  • Cricetinae
  • Cricetulus
  • Hair Cells, Auditory, Outer / drug effects
  • Hair Cells, Auditory, Outer / metabolism
  • Hearing Loss, Sensorineural / drug therapy*
  • Hearing Loss, Sensorineural / genetics*
  • Hearing Loss, Sensorineural / metabolism
  • KCNQ Potassium Channels / agonists
  • KCNQ Potassium Channels / chemistry
  • KCNQ Potassium Channels / genetics*
  • KCNQ Potassium Channels / metabolism*
  • Models, Molecular
  • Mutant Proteins / chemistry
  • Mutant Proteins / genetics*
  • Mutant Proteins / metabolism*
  • Organometallic Compounds / pharmacology
  • Patch-Clamp Techniques
  • Phenylenediamines / pharmacology
  • Pyridines / pharmacology
  • Rats
  • Rats, Wistar
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism


  • Carbamates
  • KCNQ Potassium Channels
  • KCNQ4 protein, human
  • Mutant Proteins
  • Organometallic Compounds
  • Phenylenediamines
  • Pyridines
  • Recombinant Fusion Proteins
  • ezogabine
  • pyrithione zinc