Abstract
Potassium voltage-gated channel subfamily q member 4 (KCNQ4) is a voltage-gated potassium channel that plays essential roles in maintaining ion homeostasis and regulating hair cell membrane potential. Reduction of the activity of the KCNQ4 channel owing to genetic mutations is responsible for nonsyndromic hearing loss, a typically late-onset, initially high-frequency loss progressing over time. In addition, variants of KCNQ4 have also been associated with noise-induced hearing loss and age-related hearing loss. Therefore, the discovery of small compounds activating or potentiating KCNQ4 is an important strategy for the curative treatment of hearing loss. In this review, we updated the current concept of the physiological role of KCNQ4 in the inner ear and the pathologic mechanism underlying the role of KCNQ4 variants with regard to hearing loss. Finally, we focused on currently developed KCNQ4 activators and their pros and cons, paving the way for the future development of specific KCNQ4 activators as a remedy for hearing loss.
Highlights
Hearing impairment, the most common sensory deficit in humans, affects 466 million people according to the World Health Organization (WHO) [1,2]
We focused on the developmental status of KCNQ4 activators and compared their advantages and shortcomings in terms of their potential to be used for the specific activation of KCNQ4
Van Laer et al investigated the association of 35 single nucleotide polymorphisms (SNPs) in 10 genes including GJB1, GJB2, GJB3, GJB4, GJB6, KCNJ10, KCNQ4, KCNQ1, KCNE1, KCNQ3, and SLC12A2 on 104 noise-susceptible and 114 noise-resistant individuals selected from a population of 1261 Swedish noise-exposed workers [7]
Summary
The most common sensory deficit in humans, affects 466 million people (over 6% of the world’s population) according to the World Health Organization (WHO) (https://www.who.int/news-room/fact-sheets/detail/deafness-and-hearingloss) (accessed on 20 January 2021) [1,2]. The main causes of adult-onset hearing loss are noise exposure, aging, genetic mutations, exposure to therapeutic drugs that have ototoxic side-effects, viruses, or ototoxic drugs or chemicals, resulting in damage to the auditory hair cells and neurons [1,2]. All available treatment options for hearing loss to date are limited to hearing devices, such as hearing aids and cochlear implants. Medical treatments are both lacking and required. Reduction of the activity of the KCNQ4 channel has been associated with a genetic form of hearing loss, noise-induced hearing loss, and age-related hearing loss [6,7,8]; small compounds that activate KCNQ4, Academic Editor: Srdjan M Vlajkovic. We focused on the developmental status of KCNQ4 activators and compared their advantages and shortcomings in terms of their potential to be used for the specific activation of KCNQ4
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