Cochlear inner hair cells (IHCs) transduce sound-induced vibrations into a receptor potential that controls afferent synaptic activity and, consequently, frequency and timing of action potentials in the postsynaptic auditory neurons. The receptor potential is thought to be shaped by the two voltage-dependent K⁺ conductances, I_K,f and I_K,s, which are carried by BK-type and K_V-type K⁺ channels.

Using whole-cell voltage-clamp recordings in the acutely isolated mouse cochlea we show that an additional K⁺ current is present in IHCs. This current is active at the resting membrane potential (-72 mV) and deactivates upon hyperpolarization. It is potently blocked by the KCNQ channel blockers linopirdine and XE991, while it is insensitive to tetraethylammonium (TEA) and 4-aminopyridine (4-AP), which inhibit I_K,f and I_K,s, respectively. Immunocytochemistry showed expression of the KCNQ4 subunit in IHCs, indicating that the novel K⁺ current is mediated by KCNQ4 channels. In current-clamp experiments, block of the KCNQ4-current shifted the resting membrane potential by about 7 mV to -65 mV and led to a significant activation of BK channels. Using BK channels as an indicator for intracellular Ca²⁺ concentration ([Ca²⁺]_i), it is shown that the shift in IHC resting potential observed upon block of KCNQ4 leads to an increase in [Ca²⁺]_i to micromolar concentrations. In conclusion, our results show that KCNQ4 channels set the resting membrane potential in cochlear IHCs, and thereby contribute to the maintenance of low[Ca²⁺]_i. Destabilization of the resting potential and an increase in [Ca²⁺]_i as may result from impaired KCNQ4 function in IHCs provides a novel and straightforward explanation for the progressive hearing loss (DFNA2) observed in patients with defective KCNQ4 genes.