**Abstract**

Phosphorylation is one of the most common posttranslational protein modifications. It has multiple roles in cell signaling during development as well as for maintenance of diverse functions of an organism. Protein kinases and phosphatases control phosphorylation and play critical roles in cellular processes from cell birth to cell death. Discovery of hearing-loss-associated gene variants in humans and the study of animal models have identified a crucial role of a plethora of protein phosphatases and kinases in the inner ear. In this review, those nonreceptor kinases or phosphatases are discussed, which are encoded by genes implicated in causing inherited hearing loss in humans or in mouse mutants. These studies have served to highlight the essential roles of protein kinases and phosphatases pathways to the function of the auditory system. However, the inner-earspecific substrates for most of these enzymes remain to be discovered, as do the mechanisms of disease due to the variants in the genes that encode these proteins.

**Keywords:** audition, deafness, dephosphorylation, hearing, phosphorylation

### **1. Introduction**

Different protein posttranslational modifications have been identified, which are necessary for hearing [1]. Among these, protein phosphorylation is a prominent and an important contributor to the development of the ear and control of audition. Phosphorylation is carried out by kinases using ɣ-phosphate from adenosine triphosphate as a donor to any of the three hydroxylated amino acids within the target protein. The removal of the phosphate group from the phosphorylated tyrosine, serine, or threonine residues of the proteins is catalyzed by phosphatases. Phosphorylation and dephosphorylation serve to change the polarity of the target proteins with profound consequences for protein conformation and interaction with other proteins [2].

Enzymes controlling phosphorylation can be categorized into receptor or nonreceptor protein kinases and phosphatases. Many phosphorylated proteins as well as enzymes that control these reactions have important roles in the auditory system [1]. Though variants in all genes encoding these proteins do not result in deafness; variants of some protein kinases and phosphatases have been reported to cause genetic hearing loss in humans or mice models, and these are presented here. Receptor kinases or receptor phosphatases important for hearing are discussed elsewhere [3]

and are excluded from the discussion, as are those kinases or phosphatases that catalyze the phosphorylation or dephosphorylation of non-proteinaceous biomolecules.

Variants of most of the genes encoding protein kinases or phosphatases have been reported to cause syndromic hearing loss (**Table 1**). In syndromic cases, deafness is just one of the accompanying features in a spectrum of other disorder/s affecting different organs. Syndromic deafness occurs due to the importance of the protein to other systems besides the ear. The hearing loss may be present in all individuals affected by a particular syndrome, while for others it affects only a few patients diagnosed with that syndrome. In contrast, hearing loss is the sole manifestation in an individual with nonsyndromic deafness [4].

#### **1.1 Auditory system and hearing**

The auditory system in humans has distinct parts, which include the outer ear, the middle ear, and the inner ear. Sound is perceived and processed by the ear with the final stimulus conveyed to the auditory cortex in the brain. The outer and the middle ears play important roles in conveying the sound to the cochlea within the inner ear. The cochlea is a coiled structure and contains the organ of Corti, which has the sensory receptors, termed as outer and inner hair cells. All hair cells have mechanosensitive microvilli projections at their apical ends, termed as stereocilia, which have important roles for their function [3]. True cilia, called the kinocilia, are also present, but these disappear early during maturation of the mammalian auditory system. The hair cells amplify the sound and transduce it into an electrical stimulus. The electric stimulus from the inner hair cells is finally conveyed to the brain via the spiral ganglion neurons.

#### **1.2 Hearing loss and its types**

A partial or a complete inability to hear sound is a common sensory disorder and is termed as hearing loss or deafness. Worldwide, both children and adults are affected, and approximately 430 million individuals are reported to suffer from a hearing loss (World Health Organization, 2021, https://www.who.int/news-room/fact-sheets/ detail/deafness-and-hearing-loss). Deafness is categorized into four types on the basis of the affected part. Conductive hearing loss arises as a result of impedance of passage of sound through the external ear and/or the middle ear. Sensorineural hearing loss is caused by malfunction of the inner ear (cochlea or auditory nerve). Mixed hearing loss is a combination of both conductive and sensorineural hearing loss. Central auditory processing disorder results due to damage or malfunction at the cranial nerves, the cerebral cortex, or the auditory brain stem [4].

On the basis of onset, hearing loss can be prelingual or postlingual. Prelingual hearing loss occurs during infancy, before the development of speech. Postlingual hearing loss appears after normal speech development; either during childhood or adulthood. Hearing of an individual is measured in decibels (dB HL). A normal hearing threshold is 15 dB HL while a disabling hearing loss is defined as a threshold of 35 db HL or above for the better hearing ear. Hearing loss is divided into five types on the basis of severity [4]: mild hearing loss (hearing threshold 26–40 dB HL), moderate hearing loss (hearing threshold 41–55 dB), moderately severe hearing loss (hearing threshold 56–70 dB), severe hearing loss (hearing threshold 71–90 dB), and profound hearing loss (hearing threshold >90 dB). The extent of hearing loss may be stable throughout a person's life, or it may progress and worsen over time. Genetic hearing loss contributes to at least

