The Cochlear Lateral Wall as a Biological Battery: the Mechanisms Underlying K⁺ Transport and Potential Generation

The cochlea possesses an exceptional capacity for rapid sensory transduction, enabling sound perception of at frequencies exceeding 15 kHz. This extraordinary performance depends on a specialized electrochemical environment that maintains a high endocochlear potential (EP) and facilitates efficient K⁺ circulation. The cochlear lateral wall serves as a central component, functioning as a biological battery that generates and sustains the EP via intricate ion transport mechanisms. It consists of two epithelial-like layers-the marginal cell layer and the syncytial layer-which are electrically insulated by tight junctions and interconnected via gap junctions. K⁺ enters hair cells from the K⁺-rich endolymph to initiate sensory transduction and is subsequently recycled through the perilymph and reabsorbed by the lateral wall. Our combined electrophysiological and mathematical modeling studies elucidate that the EP primarily depends on K⁺ equilibrium potentials across the apical membranes of intermediate and marginal cells, primarily mediated by K_ir4.1 and IKs channels, respectively. Pharmacological experiments confirmed that Na⁺,K⁺-ATPase and NKCC are essential for maintaining the K⁺ gradient and EP. Furthermore, our computational model successfully reproduced dynamic changes in ion concentrations and membrane potentials under hypoxic conditions and acoustic stimulation. Genetic studies further reinforce the physiological importance of lateral wall components, as mutations in associated transporters, channels, and structural proteins commonly lead to sensorineural hearing loss. Collectively, these findings underscore the cochlear lateral wall as an integrated electrochemical organ and illustrate the utility of multiscale modeling in bridging molecular mechanisms with systems-level auditory function.