# Role of Kir4.1 Channel in Auditory Function: Impact on Endocochlear Potential and Hearing Loss
## 4 Discussion
### Kir4.1 Channel
#### 4.3.3 Endocochlear Potential  
The process of generating EP in the stria vascularis is part of a cycle that involves different components of the organ of Corti. To describe this process, it is appropriate to begin with the presence of potassium from the perilymph in the interstitial space of the spiral ligament. Through channels expressed on the basal part of their membrane, such as the Na+/K+/2 Cl- co-transporter (NKCC1), the 3 Na+/2K+ATPase [18], and the inwardly rectifying potassium channel Kir5.1 [42], potassium is absorbed into the cytosol of the basal cells. From this, through a dense network of gap junctions (connexins 26, 30, 31, and 43) [15], K+ is transferred to the basal cells. The presence of tight junctions in the basal and marginal cell layers allows the formation of two physical barriers, which prevent the loss of potential created in the intrastrial space of the stria vasculature [15]. Basal cells are, in turn, connected to intermediate cells through extensive gap junctions. The fibrocytes, basal cells, and intermediate cells behave electrically as a single cellular entity due to the network of gap junctions, and the combination of these three cell types forms the first entity of the \"two-cell model\" of the stria vascularis [43]. The intermediate cells are immersed in the intrastrial space, which is a fluid with a very low potassium concentration (1-2 mM). The difference in K+ concentration between the cytosol of intermediate cells (150 mM) connected to fibrocytes and basal cells and the interstitial space causes the Kir4.1 channels to activate, ultimately allowing the passage of K+ ions out of the intermediate cells [15]. Kir4.1 channels mediate potassium efflux in intermediate cells of the stria vascularis, rather than influx as they typically do, due to the electrochemical gradients of potassium present in these cells. More specifically,  
* Marginal cells actively pump K+ ions into their cytoplasm to maintain a high intracellular K+ concentration;
* This generates a high gradient of K+ between the marginal and intermediate cells, with the intermediate cells having lower intracellular K+;
* Furthermore, the intermediate cells have a relatively negative membrane potential compared to the marginal cells;
* This double electrochemical gradient (chemical for K+ and electrical for the membrane potential) causes K+ to spontaneously efflux through the Kir4.1 channel into the intragral space. Therefore, the driving force for the efflux of K+ from the intermediate cells is the combination of a concentration gradient (high K+ intracellularly in the adjacent marginal cells) and an electrical potential gradient favoring the exit of positively charged K+ ions. At this stage, the Kir4.1 channels fulfill their fundamental function in generating the EP. Finally, marginal cells pump K+ into their interior through ATP-dependent channels on their basal membrane, keeping the K+ low in the intrastrial space. In their apical part, which is in direct contact with the endolymph, they present the potassium channels KCNQ1/KCNE1, which release the captured potassium into the endolymph, ready to be taken up by hair cells [15]. Marginal cells also form the second entity of the 'two-cell' model (Figure 4). The movement of potassium ions through passive voltage-sensitive channels such as Kir4.1 makes it the most suitable candidate for depolarizing auditory cells and, consequently, the key ion in the generation of EP [15]. If sodium ions (Na+) had been utilized for depolarizing hair cells, this would have necessitated the consumption of ATP to activate its channels and thus the movement into the cells. A significant amount of ATP would have been required, necessitating a great deal of vascularization in the region of the hair cells. This would have led to undesirable vibrations around the hair cells caused by the heartbeat transmitted through the capillaries. These vibrations would have interfered with the ability to perceive sounds, generating significant disruptions in mechanical sound transduction.