ArticleBritish journal of pharmacology2012
Restoration of ion channel function in deafness-causing KCNQ4 mutants by synthetic channel openers.
Article in British journal of pharmacology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 42 citations in OpenAlex.
- Dynamic loss of hormone receptors and reshaped drug sensitivity in male breast cancer organoids: A first case report and clinical implications.Journal of translational internal medicine · 2026Article
- Antisense oligonucleotide therapy mitigates autosomal dominant progressive hearing loss in a murine model of human DFNA2.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Recent advances in the pharmacology of voltage-gated ion channels.Pharmacological reviews · 2025Review
- Aging-induced changes in lymphatic muscle cell transcriptomes are associated with reduced pumping of peripheral collecting lymphatic vessels in mice.Developmental cell · 2025Article
- Common genetic etiologies of sensorineural hearing loss in Koreans.Genomics & informatics · 2024Review
- A versatile functional interaction between electrically silent KCellular and molecular life sciences : CMLS · 2024Article
- Vestibular hair cells are more prone to damage by excessive acceleration insult in the mouse with KCNQ4 dysfunction.Scientific reports · 2024Article
- The Pathological Mechanisms of Hearing Loss Caused byBiomedicines · 2022Review
- A potassium channel agonist protects hearing function and promotes outer hair cell survival in a mouse model for age-related hearing loss.Cell death & disease · 2022Article
- Cell death-inducing cytotoxicity in truncated KCNQ4 variants associated with DFNA2 hearing loss.Disease models & mechanisms · 2021Article
- miR-153/KCNQ4 axis contributes to noise-induced hearing loss in a mouse model.The journal of physiological sciences : JPS · 2021Article
- Novel KCNQ4 variants in different functional domains confer genotype- and mechanism-based therapeutics in patients with nonsyndromic hearing loss.Experimental & molecular medicine · 2021Article
- Age-related hearing loss pertaining to potassium ion channels in the cochlea and auditory pathway.Pflugers Archiv : European journal of physiology · 2021Review
- Chemical modulation of Kv7 potassium channels.RSC medicinal chemistry · 2021Review
- Activation of KCNQ4 as a Therapeutic Strategy to Treat Hearing Loss.International journal of molecular sciences · 2021Review
- Molecular simulation of the Kv7.4[ΔS269] mutant channel reveals that ion conduction in the cavity is perturbed due to hydrophobic gating.Biochemistry and biophysics reports · 2021Article
- Stochasticity Versus Determinacy in Neurobiology: From Ion Channels to the Question of the "Free Will".Frontiers in systems neuroscience · 2021Article
- Kv7 Channels and Excitability Disorders.Handbook of experimental pharmacology · 2021Article
- Cooperativity of KScience advances · 2020Article
- β-Secretase BACE1 Is Required for Normal Cochlear Function.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2019Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeDFNA2 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
resultsVarious 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.
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