Potential Mechanisms of Hearing Loss Due to Impaired Potassium Circulation in the Organ of Corti

Abstract

Hearing loss (HL) is a common condition that significantly affects an individual’s quality of life. Impaired potassium circulation in the organ of Corti (OC), including the movement of potassium into hair cells (HCs) and from hair cells to supporting cells (SCs), can contribute to hearing loss. This chapter aims to provide a better understanding of cochlear potassium ion homeostasis and its dysfunction in this context. Sensorineural hearing loss (SNHL) is caused by damage to the inner ear or the auditory nerve. Various factors contribute to it, including aging, exposure to loud noise, genetics, medications, and infections. In all of them, some level of potassium circulation alteration is present. Potassium plays a crucial role in hearing function as it is the moving charge that depolarizes hair cells in response to sound perception. It generates the endocochlear potential (EP) which provides the driving force for potassium movement. Disruptions in potassium circulation due to molecular alterations in ion channels and transporters can lead to hair cells dysfunction and cell death. Moreover, drugs that affect potassium circulation can also cause hearing loss. Understanding the molecular and tissue changes resulting from potassium circulation deficits is essential for developing targeted treatments and preventive measures for potassium-related hearing disorders.

1. Introduction

Hearing loss (HL) is a common condition nowadays that reduces hearing capacity. HL can be caused by a variety of factors, and it can have a significant impact on a person’s quality of life [1, 2]. In this chapter, we will explain the importance of potassium (K⁺) circulation for proper hearing function and how it can cause HL, primarily focusing on K⁺ movement from hair cells (HCs) to supporting cells (SCs). By the end of this chapter, we aim to have a better understanding on cochlear K⁺ ion homeostasis and how its dysfunction contributes to very common HL processes.

Sensorineural hearing loss (SNHL) is the most common type of HL, affecting millions of people worldwide [2, 3, 4]. SNHL occurs when there is damage to the inner ear or the auditory nerve [5]. Unlike conductive HL, which occurs when sound is blocked from reaching the inner ear, SNHL occurs when sound is not effectively transmitted to the brain (Figure 1) [2, 6]. This type of HL can be caused by a variety of factors, including aging, exposure to loud noise, genetics, some drugs, and certain medical conditions [7, 8, 9, 10]. Age-related hearing loss (ARHL), also known as presbycusis, is a common sensory disorder among the elderly. It is characterized by a decline in hearing sensitivity and speech discrimination, delayed central processing of acoustic information, and impaired localization of sound sources. Multiple mechanisms have been proposed for age-related cochlear degeneration, and it appears that both genetic and environmental factors play a role. Noise-induced hearing loss (NIHL) is a significant occupational health risk in developed countries. NIHL can also result from unsafe recreational, social, and residential noise exposures. People with excessive exposure to noise are frequently the population with a lifestyle which may affect auditory function. Exposure to loud noises, such as explosions or prolonged exposure to high sound levels, can cause damage to the delicate structures within the inner ear. This can lead to temporary or permanent HL, depending on the severity and duration of the exposure. Genetic factors play a significant role in the development of SNHL. Mutations in genes such as those coding for calcium (Ca²⁺) channel and K⁺ channels in sensory HCs of the cochlea can cause hereditary deafness, but many others have been elucidated [6, 11, 12, 13]. Also certain medications, such as aminoglycoside antibiotics and some drugs for cancer treatment, can be toxic to the inner ear, causing damage to the HCs and auditory neurons. This damage can be temporary or permanent, depending on the drug and the dosage. Lastly on the causes of HL, infections, such as prenatal toxoplasmosis, rubella, meningitis or cytomegalovirus, can cause inflammation and damage to the inner ear, leading to SNHL [6].

Figure 1.

Auditory pathway and potassium circulation in cochlea. Schematic representation of the auditory system, composed by: The outer, the middle, and the inner ear; and scheme of the auditory pathway to auditory cortex in the brain. Inset of the cochlea’s cross section depicts the scala vestibuli and scala tympani (both filled with perilymph) and the scala media filled with endolymph, containing the OC: IHCs, OHCs, and SCs. Schematic representation of the K⁺ recirculation from the OHCs to the endolymph through SCs and Stria vascularis (green arrows). This figure is original for this work.

K⁺ is essential for the proper functioning of hearing. This ion is found in high concentration in the endolymph contained in the scala media of the cochlea. This high concentration of K⁺ generates the endocochlear potential (EP), which, in conjunction with the HCs resting membrane potential, creates a strong driving force for the entry of this ion when sound causes bending of the stereocilia bundle [14]. After sound perception, K⁺ leaves the HCs and returns to the stria vascularis through gap junctions (GJs) and transporters present in the surrounding SCs. The flow and recycling of K⁺ ions play a vital role in the conversion of sound vibrations into electrical signals that can be transmitted to the brain for auditory perception [14, 15, 16, 17, 18, 19, 20, 21, 22].

Molecular alterations in channels and transporters involved in the process of K⁺ circulation lead to HCs dysfunction and, ultimately, cell death. Moreover, drugs that alter K⁺ circulation can result in HL [23, 24, 25, 26, 27, 28]. Most of these changes impacts primarily on outer hair cells (OHCs) function and survival [29]. For these reasons, we focus on this sensory cell type in this chapter. Understanding the molecular, tissue, and innervation changes that occur in HCs due to deficits in K⁺ circulation is crucial for advancing our knowledge of hearing loss mechanisms, developing targeted treatments, identifying preventive measures, and enabling personalized interventions. Such understanding has the potential to improve the diagnosis, management, and overall quality of life for individuals affected by K⁺-related hearing disorders.

2. Anatomy and physiology of the organ of Corti

The organ of Corti (OC) is a complex structure located in the spiral-shaped cochlea of the inner ear, playing a crucial role in the process of hearing by converting sound vibrations into interpretable electrical signals. The OC rests on the basilar membrane, a thin and flexible membrane spanning the length of the cochlea. It separates the scala media from the scala tympani. Within the OC, there are specialized sensory cells known as HCs, specifically the inner hair cells (IHCs) and outer hair cells (OHCs), responsible for the conversion of sound vibrations into electrical signals. Above the OC lies the tectorial membrane, a gelatinous structure that extends over the HCs, playing a pivotal role in the mechanotransduction process (see further). SCs encompass the OC, providing structural support, and safeguarding the HCs, while also regulating the ionic composition of the perilymph to maintain proper HC function [15]. Furthermore, the neuronal connection to the central nervous system is facilitated by the spiral ganglion (SG), a cluster of neurons situated within the cochlea. The fibers of the SG neurons establish connections with the HCs, transmitting the electrical signals generated by the HCs to the auditory nerve (Figure 1). Collectively, these components work harmoniously to convert sound vibrations into electrical signals, facilitating their transmission to the brain and enabling the perception and interpretation of sounds [30].

2.1 Structure and function of hair cells

As mentioned above, there are two types of sensory HCs in the cochlea that detect sound vibrations: IHCs and OHCs. These cells possess small, finger-like projections called stereocilia on their apical surface, facing endolymph, the high-K⁺ fluid that filled the scala media (Figure 2). When stimulated by sound vibrations, the stereocilia of the HCs move, opening mechanoreceptor channels and initiating the generation of electrical signals. While both types of HCs depolarize in response to K⁺ entrance, their specific functions and contributions to auditory processing differ. IHCs primarily serve the role of transmitting auditory information to the brain, whereas OHCs play a role in amplifying sound signals and fine-tuning the sensitivity of the cochlea [31, 32]. The depolarization caused by the entrance of K⁺ is a unique feature among mammals and allows ion movement following its electrochemical gradient from endolymph to cytosol at the apical membrane and exit at the basal membrane to the extracellular fluid between HCs and SCs. The depolarization of the HCs leads to their activation upon reaching the receptor potential (RP), which represents the membrane voltage threshold that triggers the opening of CaV1.3 voltage-dependent calcium channels in IHCs [33] and initiate the process of electromotility in OHCs (see further) [32].

Figure 2.

Potassium movement in hair cells. Illustration depicting the IHC (left), with the influx of K⁺ through the mechanosensitive channels, and the efflux of this ion mediated by the channels responsible of the I_K,n, I_K,s, an I_K,f currents. Also, the Ca²⁺ channels which are responsible for the neurotransmitter release from the ribbon and the afferent synapses are depicted. On the right, schematic representation of the OHC, with the influx of K⁺, also through mechanosensitive channels, and its efflux mediated by different K⁺ channels, mainly KCNQ4. Efferent synapse through MOC terminals is also depicted, and the α9α10 nAChR is responsible for the modulation of hearing sensitivity. This figure is original for this work.

2.2 Dieter’s cells structure and function

The sensory cells in the OC are surrounded by a heterogeneous group of cells denominated SCs. Among them, there is a subgroup constituted by the Dieter’s cells (DCs), disposed across the OC in three rows under the OHCs. The DCs play an important role keeping the structure of the organ, acting mainly as a support, but also in homeostasis of ions and other molecules, and modulation of extracellular matrices (Figure 3) [34, 35].

Figure 3.

Draining of potassium by the Dieter’s cells. Illustration of the OHC location and DC in the OC, depicting the efferent innervation that contacts both cells. Gap junctions, composed by connexin monomers (Cx26 and Cx30), between DCs are also showed in the figure. Inset depicts the small space between the OHC and DC, showing the main channels involved in the K⁺ circulation, and the efferent modulation in the hearing process. This figure is original for this work.

DCs are characterized for presenting an elongated body, extending from the reticular lamina to the basilar membrane [36]. Structurally, these cells have an apical region, consisting on an extension projecting from their medial region to the reticular lamina, denominated “phalangeal process” which forms tight junctions with the OHCs at the level of the reticular lamina [37], a medial region cup-shaped, which contains and binds through tight and adherents junctions to the base of the OHCs, and a basal region holding the nucleus and most of organelles [38, 39, 40]. The medial region of the DCs envelopes nerves contacting them and the basal pole of OHCs [41]. The cytoskeleton of these cells is commonly called “Dieter’s stalk” [36] and consists of microtubules, intermediate filaments and actin, and extends from the basilar membrane to the reticular lamina through the phalangeal process. The cytoskeletal structure has a conical shape thickening in the site contacting the basilar membrane called “basal cone” (Figure 3) [42].

2.3 Sound transduction in the organ of Corti

When sound waves enter the cochlea, their vibrations are transmitted through the perilymph of the scala tympani to the basilar membrane, causing the HCs to bend their stereocilia against the tectorial membrane. As explained previously, this movement opens the mechanosensitive channels located on the stereocilia of the HCs, activating K⁺ influx [6, 16]. The RPs trigger the release of the neurotransmitter glutamate by the IHCs, while activating the amplification process in the OHCs [43].

Vesicle release in IHCs occurs in the basolateral membrane, which contains the active zones characterized by the presence of synaptic ribbons that supply ultrafast and precise synaptic vesicles for exocytosis, to release glutamate into the synaptic cleft (Figure 2, left) [43, 44]. The released neurotransmitters then stimulate postsynaptic afferent nerve fibers from the SG neurons, sending electrical signals to the brain for sound interpretation through the auditory pathway [16, 45]. The primary function of OHCs is to amplify and fine-tune the sound signals before they reach the IHCs. The physiology of OHCs involves several key mechanisms that contribute to their capabilities [46]. It includes three main features:

1. Electromotility: one of the defining properties of OHCs is their ability to change shape in response to RPs. It is enabled by the presence of a protein called prestin in the lateral membrane of OHCs (Figure 2, right). When a sound stimulus is detected, a RP is generated across the cell membrane, leading to a contraction or elongation of the OHCs. This mechanical movement enhances the sensitivity and selectivity of the cochlea to different sound frequencies.

2. Basilar membrane motility: electromotility of OHCs has a direct effect on the mechanics of the basilar membrane. The movement of OHCs alters the tension and stiffness of the basilar membrane, increasing vibration intensity of IHCs in the OC. This process is known as the cochlear amplifier or the OHC amplifier.

3. Olivocochlear feedback: it involves neural connections from the brainstem to the cochlea that serve as a feedback mechanism. This efferent innervation modulates HCs excitability (Figure 2, right).

These mechanisms, collectively named “the active process,” are crucial for our ability to detect and perceive sounds accurately, and it can be disrupted by factors such as noise exposure or genetic mutations.

2.4 Efferent innervation of the organ of Corti

The auditory system has two efferent neuronal components originated in the lateral and medial nuclei of superior olivary complex (LOC and MOC, respectively) [47]. LOC fibers make synaptic contacts with afferent fibers that contact IHCs in adult, while MOC fibers make synaptic contacts with the OHCs [48]. LOC function is still not fully understood. The main effect of MOC efferent innervation is to inhibit the cochlear response by reducing the amplification gain of the OHCs. This effect is observed as a reduction in the motility of the basilar membrane and as a transient loss of sensitivity of the auditory nerve to sound [49]. The efferent fibers directly contact the OHCs, producing inhibitory synaptic currents once activated [50]. Paradoxically, this inhibition is mediated by an excitatory current generated by the nicotinic acetylcholine receptor (nAChR) composed by the α9 and α10 subunits [51, 52]. The α9α10 nAChR is a cationic channel with high Ca²⁺ permeability [53, 54]. In the OHCs, the entry of Ca²⁺ through this channel leads to the activation of Ca²⁺-dependent K⁺ channels, SK2 and BK, resulting in hyperpolarization of the cell membrane through the efflux of K⁺ ions through these channels [55, 56]. It is believed that Ca²⁺ entry through α9α10 nAChR triggers the release of cytoplasmic Ca²⁺ from cisterns located near the efferent synapses, and this ion would activate the SK2 channels [57]. The release of cytoplasmic Ca²⁺ from these cisterns is modulated by the ryanodine family of channels [58]. In this way, the efferent system modulates the activity of the OHCs, preventing excessive depolarization, for example, during prolonged exposure to a sound stimulus [47]. It has been demonstrated that an exacerbation of efferent system activity protects against acoustic damage [59]. In a model of over activation of nicotinic channels, generated by a mutation in the α9 subunit of the α9α10 receptor, increased sensitivity to acetylcholine and decreased channel desensitization were observed. Animals with this mutation had a higher acoustic threshold, showing greater protection against acoustic damage [59]. Conversely, it has also been shown that auditory overstimulation causes synaptopathy in young mice, resulting in a decrease in synaptic contacts of the OHCs [60, 61].

Besides the innervation of the sensory cell, nerve fibers making contact with DCs and other SCs were identified more than 40 years ago [62] and have since been confirmed through the labeling of synaptic terminals in the DCs of both cats and humans, using specific markers [63, 64]. Further investigations have revealed that these fibers originate from the MOC efferent system [65]. Recent findings have shown that the synapses formed by these fibers are functional and cholinergic in nature. DCs express the same type of nAChR as OHCs, specifically the α9 nAChR was identified so far [66]. The efferent innervation influences the activity of gap junction channels, thereby modulating the movement of K⁺ ions through DCs. Consequently, the available evidence suggests that the MOC system may indirectly regulate the activity of OHCs by potentially exerting control over the membrane potential of DCs.

2.5 Potassium circulation in the organ of Corti

K⁺ circulation plays a crucial role in hearing as it is closely linked to the proper function of the auditory system. As mentioned above, the scala media contains endolymph, a high K⁺ fluid, bathing the apical membrane of both HCs. [14, 67, 68]. The influx of K⁺ into HCs depolarizes them resulting in either the release of glutamate by IHCs or electromotility in OHCs, as the RP is reached. K⁺ enters through a mechanoelectrical transduction complex located at the tip of stereocilia bundle [16, 30, 69]. This complex, still not fully resolved, forms a nonselective cation channel where K⁺ and Ca²⁺ enter [30, 69]. After the entry of K⁺ ions into the HCs, their removal becomes necessary for the hearing perception to continue. This is where K⁺ circulation plays a crucial role, to repolarize the resting membrane potential. Specialized channels and transporters are responsible for pumping the K⁺ ions out of the HCs and back into the endolymphatic fluid of the cochlea (Figure 1, inset) [14, 15, 22].

One of the channels responsible for these functions is the KCNQ4 voltage-gated K⁺ channel. KCNQ4 is primarily responsible for generating the main K⁺ conductance current in OHCs known as I_K,n. It is predominantly expressed at the basal pole of OHCs, where it plays a crucial role facilitating K⁺ efflux (Figure 2) [70, 71, 72, 73, 74, 75]. Although to a lesser extent, KCNQ4 is also expressed in IHCs, as determined by gene and protein expression and functional properties of the IHCs (Figure 2) [71, 73, 76, 77, 78, 79, 80, 81, 82]. In this cell, it generates the K⁺ current I_K,n, one of the three main K⁺ currents in IHCs [16]. Impaired surface expression or reduced activity of the KCNQ4 channel leads to functional deterioration of the OC and has been associated with different types of HL: age-related hearing loss [23, 83, 84, 85, 86], noise-induced hearing loss [87, 88, 89], and genetic hearing loss [71, 85, 86, 90, 91].

Other K⁺ channels involved in the K⁺ efflux are the Ca²⁺-activated K⁺ channels BK and SK2 (Figure 2). They differ from each other in their affinity to Ca²⁺, single-channel conductance, and voltage sensitivity [55]. In IHCs, they are responsible for generating the I_K,f current that contribute to cell repolarization [92]. Both channels are involved in the efferent regulation of OHCs. BK channels show tonotopic gradients of progressively increasing expression from low-frequency (apical zone) to high-frequency (basal zone) cochlear regions [55, 92, 93, 94, 95, 96]. On the contrary, SK2 channels increase their expression from basal to apical cochlear turns [97]. In the mature OC, BK channels are found in the neck of IHCs and in the basal pole of OHCs, in the same area where the efferent terminals are located [56]. Similar localization was observed for SK2 channels in OHCs [56, 94]. These channels are functionally coupled to ligand-gated ion channels to cause rapid postsynaptic inhibition [55, 97]. The efferent synapse activates BK and/or SK2 channels, depending on cochlear region, through α9α10 nAChR opening and Ca²⁺ entry [51, 52] hyperpolarizing the HCs [97, 98].

Once K⁺ ions leave the HCs, they diffuse through the extracellular space. One appealing hypothesis for K⁺ circulation suggests that these ions are reabsorbed by SCs located in the epithelial lining of the cochlea and actively transport them back into the endolymph (Figures 1 and 3) [14]. The closest cells to OHCs are DCs. The membrane of the DCs on the contacting surface with OHCs expresses the K-Cl cotransporters, KCC3 and KCC4 (Figure 3). These cotransporters belong to a protein family that plays a role in regulating cytoplasmic ion concentration, cell volume, and salt transport through the epithelia [99]. It has been hypothesized both cotransporters play the same role: capture K⁺ extruded from OHCs for them to hyperpolarize. In addition of these cotransporters, it has been observed the presence of another K⁺ channel expressed in the body of DCs and especially in the cup region, Kir4.1. It has been suggested this channel would be involved in the regulation of cellular physiology and presumably affect K⁺ uptake [15, 100]. K⁺ intake in DCs also relies on ATP-dependent channels, purinergic P2 receptors (Figure 3). In the extracellular space, ATP acts as a signaling molecule which allows these channels activation at the resting membrane potential for ions entrance, mainly of K⁺ [101].

Dieter’s cells form a syncytium, meaning that their cytoplasm is electrically connected through GJ, allowing the initiation of potassium recycling toward the stria vascularis in favor of its electrochemical gradient. There are different isoforms of CONNEXINs (Cx) in the inner ear, although only two are expressed in DCs: Cx26 and Cx30 [102]. Their expression levels differ along the cochlea, as in SCs [103], and both are considered indispensable for hearing [20, 102]. Cx26 and 30 are capable of assemble as homomeric GJ channels (Cx26/Cx26 or Cx30/Cx30) and also as heteromeric ones (Cx26/Cx30); GJs are important for ion circulation through SCs, as well as other molecules, such as miRNA [20, 104, 105].

3. Potassium circulation deficits and molecular changes in the organ of Corti

As we mentioned before, the circulation of K⁺ is crucial for maintaining the proper functioning of the HC and the overall auditory system. Disruptions in K⁺ circulation can lead to hearing problems and disorders [22]. For example, impairment in the transporters responsible for removing K⁺ can lead to its accumulation in the HCs, disrupting the electrical signaling process and resulting in HL. Furthermore, certain medications, such as aminoglycosides or some diuretics, can interfere with K⁺ circulation and affect hearing function as a side effect [24, 26, 27, 106].

3.1 KCNQ4 channel alterations leads to hearing loss

The major pathway for K⁺ exit from OHCs is the KCNQ4 channel [71]. Mutations in the gene encoding this channel subunit underlie a slowly progressive dominant form of human deafness, named DFNA2. Patients carry dominant negative (dn) mutations that lead to HL over years [86, 107, 108, 109]. Mouse models with alterations in the Kcnq4 gene or in the channel function by pharmacological agents, such as salicylate or aminoglycosides, have been helpful in studying the pathophysiological mechanisms underlying KCNQ4 channel dysfunction [26, 28, 71, 110, 111]. The loss of KCNQ4 function in OHCs can result in sustain depolarization due to intracellular K⁺ accumulation, which consequently leads to their degeneration due to chronic cellular stress [71]. When KCNQ4 is absent, cochlear OHCs degenerate first at the basal turn of the cochlea, which mediates high-frequency hearing, and progress to the apical turn with time, affecting IHCs and SG neurons [71, 110]. At this moment, three transgenic mouse models carrying dn Kcnq4 gene mutations found in DFNA2 patients have been analyzed [71, 112, 113]. Two of them are located in the pore region, W276S and G286S [71, 112], while the other, G228D, was in the intracellular S4–S5 linker region [113]. In heterozygosity, the KCNQ4 mutant subunits in each case assemble with either wild-type, mutant, or combination of both subunits, forming homo- or heteromeric channels, which drastically reduce their conductance and in consequence, the I_K,n current of OHCs. Similar to KCNQ4 knock-out (KO) model, these mouse models exhibit HL with OHCs loss over time, starting in the basal turn and progressing over time to middle and apical turn albeit with a slower time course than KO. The first two models exhibit a relatively fast loss of OHCs with the preservation of IHCs. For the last model, IHCs loss was also observed starting four to eight weeks later than in OHCs [113]. The absence or mutations of the KCNQ4 channel subunit impact in the membrane potential, being differently reduced in OHCs and IHCs [71]. This depolarization would increase Ca²⁺ influx through voltage-gated Ca²⁺ channels into these cells and may thereby underlie the degeneration processes. Notably, in these models, hearing impairment tend to be uniform across all frequencies, implying dysfunction along the entire cochlea. However, the loss of OHCs invariably begins at the basal turn and gradually progresses over time. These results indicate an uncoupling between cellular functionality and survival, highlighting our incomplete understanding of the cellular and molecular mechanisms involved in this process.

Same results were obtained when KCNQ4 channels function was diminished. For example, pharmacological inhibition of KCNQ4 by linopirdine in an adult guinea pig model has been shown to cause acute HL through compromised function and severe OHCs degeneration in the basal turn, which corresponds to the high-frequency range of the cochlea [28]. Given its important role in K⁺ circulation and the pathological consequences of impaired KCNQ4 channel activity, activation of the KCNQ4 channel has been proposed as a treatment for HL [23]. In this regard, the KCNQ4 channel opener retigabine has been useful in reversing salicylate-induced cytotoxicity [25]. Furthermore, channel openers have been used to mitigate HL in an ARHL mouse model [23, 114]. These findings lead to the hypothesis that pharmacological activation of KCNQ4 channels may preserve hearing function and prevent OHCs loss in ARHL and other forms of HL [23, 114]. In addition, gene therapy to correct a dn Kcnq4 mutation in a mouse model partially succeed to correct HL degeneration that develops in this condition [112].

3.2 BK and SK2 channels malfunction affects the hearing process

Regarding BK channels, pharmacological blockade of them has minimal effect on OHC functionality [115], and genetic deletion of the channel has little effect on cochlear sensitivity [92]. However, as BK channels contribute to the inhibitory signaling on OHCs through the MOC efferent pathway [97], mice lacking BK channels have reduced MOC inhibition with smaller efferent synapses. However, they remain functional [56, 116]. These data are in line with previous reports of mice lacking the BK channel pore-forming α-subunit that do not exhibit a congenital HL but rather develop mild progressive high-frequency HL. In contrast, mice lacking the auxiliary BK channel β1 gene do not exhibit any hearing deficits and have a normal cochlear phenotype [96].

Deletion of SK2 channels in mice showed that action potential activity was abolished in these animals [117]. In addition, efferent innervation of OHCs was severely reduced in young KO mice. OHCs from this model were completely insensitive to exogenous ACh, implying absent or otherwise dysfunctional nAChR [95]. Another animal model lacking SK2 channel showed that they are necessary for long-term survival of olivocochlear fibers and synapses. Loss of the SK2 gene also results in loss of electrically driven olivocochlear effects in vivo, and down-regulation of ryanodine receptors involved in Ca²⁺-induced Ca²⁺ release, the main inducer of nAChR evoked SK2 activity [94].

In conclusion, BK and SK2 channels are necessary for proper function of the OC and seem to have some degree of overlapping function in controlling OHC excitability. However, as efferent inhibition is impaired, dysfunction of these channels would lead to HL as well.

3.3 Dieter’s cells channels malfunction in potassium circulation

Mouse models have played a crucial role in unraveling the function of the DCs in the OC function. Models lacking the expression of KCC3 and KCC4 (Kcc3^−/− and Kcc4^−/−, respectively) showed the same phenotype, degeneration of HCs, probably due to osmotic stress or membrane depolarization [99, 118]. In Kcc3^−/− mouse model, cell degeneration occurred slowly compared with Kcc4^−/− mice; it is not known if it is due to more expression of KCC4 or different properties in the isoforms. In addition, KCC3 is expressed in type I and III fibrocytes in the stria vascularis, and both also degenerate in the absence of the protein [118].

As previously mentioned, K⁺ moves between DCs using GJ channels (Figure 3) [14, 119, 120]. Mouse models have also been extremely useful to decipher the role of Cx in DCs. It has been reported that Cx30^−/− mice develop profound HL and exert a negative modulation of Cx26 expression. On the other hand, Cx26^−/− mice develop a cell degeneration that leads to HL, despite the remaining GJ remain permeable to ion flux probably due to Cx30 presence [121, 122]. It is worth noting that mutations in connexin 26 are the most common mutations found in genetically inherited HL. [123]

In addition to their role in ion and molecules flux among SCs, it has been reported that GJs in DCs could modulate OHCs electromotility: changes in gap junction permeability modify membrane potential, leading to DCs depolarization which reduces OHCs electromotility associated with nonlinear capacitance and otoacustic emissions [124]. The mechanism by which this occurs is not only related to K⁺ accumulation in the extracellular space between OHCs and DCs but also to their mechanical connection. Structural cytoskeleton modifications in DCs, by its destruction, or Ca²⁺ influx which alters phalangeal process stiffness [125] alters OHCs electromotility. Also, uncoupling of the mechanical junctions described in Section 2.2 between DCs and OHCs generates the same effect [101, 124].

In conclusion, it has been demonstrated that DCs are not merely passive transporters of K⁺ ions during the cochlear circulation process, but they also actively participate in modulating the electromotility of OHCs [121].

4. Conclusions

Impaired K⁺ circulation in the organ of Corti can lead to HL by disrupting essential processes involved in sound transduction and cochlear function. K⁺ homeostasis plays a critical role in the proper function of HCs and the conversion of sound vibrations into electrical signals. K⁺ is the main electric charge that, contrary to what happens in all other excitable cells in our body, directly depolarizes sensory cells. Molecular alterations in ion channels and transporters responsible for K⁺ movement can result in HCs dysfunction and cell death. In this chapter, we detailed the main channels and transporters involved in the movement of K⁺ from the endolymph to the network of SCs that facilitate its return to the endolymph. In OHCs, K⁺ entry from the endolymph is mediated by mechanotransduction channels in the apical region, while its extrusion is mediated by KCNQ4 channel in the basal region, facing the extracellular space. The efferent system also plays a role in modulating K⁺ movement to finely tune hearing. It activates additional K⁺ currents mediated by either SK2 or BK channels. K⁺ is cleared from the extracellular space by DCs whose membrane contain the K⁺-Cl⁻ cotransporter KCC3 and KCC4, the K⁺ channel Kir4.1, and the purinergic P2 receptors. Once taken by DCs, K⁺ moves through GJ composed of Cx26 and Cx30 back to the stria vascularis, where it is pumped back into the endolymph. Mouse models bearing alterations in these channels have helped to determine their importance in the K⁺ circulation process, which generally leads to progressive HL due to OHC dysfunction and death. Overall, a comprehensive understanding of the mechanisms underlying K⁺ circulation and its disruption in the OC is essential for advancing our understanding of HL, improving diagnosis and management, and ultimately enhancing the quality of life for individuals affected by K⁺-related hearing disorders.

Acknowledgments

This work was supported by the grant PIP 0091 from CONICET and the grant PGI 24/B333 from UNS to G.S. and the grant PIBAA from CONICET to L.D. E.R. is a postdoctoral fellow from CONICET.

Conflict of interest

The authors declare no conflict of interest.

Appendices and nomenclature

HL: hearing loss, HCs: hair cells, IHCs: inner hair cells, OHCs: outer hair cells, MOC: medial olivochochlear complex, LOC: lateral olivochochlear complex, OC: organ of Corti, K⁺: Ppotassium, Ca²⁺: calcium, nAChR: nicotinic acetylcholine receptor, DC: Dieter’s cells, SCs: supporting cells, KO: knock-out, GJ: gap junction. RP: receptor potential. SNHL: sensorineural hearing loss, ARHL: age-related hearing loss, NIHL: noise-induced hearing loss, EP: endocochlear potential, Cx: connexin, dn: dominant negative.