# Role of Kir4.1 Channel in Auditory Function: Impact on Endocochlear Potential and Hearing Loss
## 4 Discussion
### Kir4.1 Channel
#### 4.3.5 Pathophysiology
These data match those obtained in Xenopus oocytes, in which the K current levels of all disease-associated mutant channels, such as R65P, G77R, and A167V/R297C, were lowered, with a range of a 1 to 23% difference compared to the wild-type level [25]. In order to imitate the heterozygous state that exists among R199X, C140R, and G77R, what has been investigated is the coexpression of mutant and wild-type subunits that results in a decrease in currents to 55, 40, and 20% of wild-type levels, suggesting that carriers of these mutations may have an abnormal phenotype [25]. Meanwhile, the coexpression of Kir4.1 mutations with Kir5.1 resulted in a reduction in currents that was at least as significant as when the mutants were expressed alone. The currents of all mutants except R199X were significantly reduced when pH was reduced from approximately 7.4 to 6.8, but wild-type channels remained unaffected [25]. The authors suggest that these mutations provide an explanation for the molecular defects that make up the EAST/SeSAME syndrome. Their conclusion is that the loss of channel function for the disease-associated mutant Kir41 channels could be attributed to altered pH gating, which could have significant physiological consequences [25; 63]. By using mutant mice that lack the KCNJ10 K+ channel, how it generates EP and delivers K+ to marginal cells was evaluated. The measurement of EP and endolymphatic K+ was performed on homozygous (\(-/-\)) mutant mice, with wild-type (+/+) and heterozygous (\(-/+\)) littermates being the controls. The KCNJ10 channel and other transport pathways are responsible for the generation of EP and the establishment of differences in K concentration across the channel, making it an important mechanism for marginal delivery of K+ to the atrial marginal cells [43]. The marked anatomical anomalies present in the inner ear of the Kir4.1 knockout mouse indicate that the pathology matches the spatial and temporal distribution of Kir4.1. Kir4.1 was suggested to be an essential component of the stria vascularis and is the main K+ channel in glial cells surrounding spiral ganglion neurons and axons [33]. Finally, recent research has shown that Kir4.1 plays a role in progressive hearing loss caused by aging in the CBA/caj mouse model and in human temporal bone. Changes in structure and function have been observed in intermediate cells of the vascular stria, the outer sulcus of the cochlear lateral wall, and the satellite cells of the spiral ganglion. In particular, a significant decrease or alterations in the expression of the kit4.1 potassium channel have been identified. The data indicate that progressive hearing loss was caused by the degeneration/dysfunction of ion channels, which provides new insights into understanding metabolism and pathophysiological processes related to aging [64]. _In vitro_ studies have shown that aminoglycosotide antibiotics target Kir4.1 channels, which could have an impact on potassium transport and lead to an imbalance of homeostasis in various tissues, providing an explanation for the ototoxicity effect of these commonly used antibiotics [65; 66]. In both _in vitro_ and _in vivo_ mouse models, Kir4.1 was demonstrated to act as a replacement for deficient K+ channels in supporting cells to rectify the imbalance in K+ concentration [66].