Activation of KCNQ4 as a Therapeutic Strategy to Treat Hearing Loss

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.

Subtype specific responses in hKv7.4 and hKv7.5 channels to polyunsaturated fatty acids

“…KV7.2 and KV7.3 are broadly expressed in neurons where they form heterotetrameric KV7.2/7.3 channels, and mutations to these channels may give rise to epilepsy or chronic pain (Biervert et al, 1998, Wang et al, 1998, Nappi et al, 2020. KV7.4 is of particular importance in the auditory system where it forms homotetrameric channels responsible for a K + conductance at the resting membrane potential of cochlear outer hair cells (OHCs) (Kubisch et al, 1999, Kharkovets et al, 2000, Rim et al, 2021. Mutations that perturb the trafficking or function of KV7.4 in OHCs are associated with a subtype of progressive hearing loss known as DFNA2 (Kubisch et al, 1999, Kharkovets et al, 2006, Gao et al, 2013, Rim et al, 2021.…”

“…KV7.4 is of particular importance in the auditory system where it forms homotetrameric channels responsible for a K + conductance at the resting membrane potential of cochlear outer hair cells (OHCs) (Kubisch et al, 1999, Kharkovets et al, 2000, Rim et al, 2021. Mutations that perturb the trafficking or function of KV7.4 in OHCs are associated with a subtype of progressive hearing loss known as DFNA2 (Kubisch et al, 1999, Kharkovets et al, 2006, Gao et al, 2013, Rim et al, 2021. KV7.5 is more widely spread through the central nervous system and is particularly important in regulating excitability in the hippocampus (Schroeder et al, 2000, Tzingounis et al, 2010, Fidzinski et al, 2015.…”

Molecular Mechanisms of Sensorineural Hearing Loss and Development of Inner Ear Therapeutics

“…The voltage-gated potassium channel KCNQ4 has an essential role in regulating auditory function in the inner ear, by contributing to potassium recycling and maintenance of cochlear homeostasis. Reduced activity of the KCNQ4 channel has been associated with a genetic form of hearing loss, noise-induced hearing loss, and age-related hearing loss [ 11 ]. Rim and colleagues presented a comprehensive review of 90 publications looking at the KCNQ4 as a potential therapeutic target for the treatment of hearing loss [ 11 ].…”

“…Reduced activity of the KCNQ4 channel has been associated with a genetic form of hearing loss, noise-induced hearing loss, and age-related hearing loss [ 11 ]. Rim and colleagues presented a comprehensive review of 90 publications looking at the KCNQ4 as a potential therapeutic target for the treatment of hearing loss [ 11 ]. In this review, the authors updated the current concepts of the physiological and pathophysiological roles of KCNQ4 in the inner ear and focused on the role of KCNQ4 activators in therapeutic management of different forms of hearing loss.…”

Noise-Induced Hearing Loss and Associated Genes

“…Antioksidan sistem bu serbest radikalleri nötralize edemediğinden koklear duyu epiteli hasar görür [3]. Sonuç olarak, süperoksit dismutaz, glutatyon Stransferaz ve katalaz gibi reaktif oksijen türlerinin düzenlenmesinde yer alan genler, kokleanın gürültüye bağlı işitme kaybına karşı hassasiyetini etkileyebilir [26]. GBİK, en yaygın mesleki koşullardan biri olup geniş bir endüstri yelpazesinde ortaya çıkmaktadır.…”