Identification of a key residue in Kv7.1 potassium channel essential for sensing external potassium ions

K_v7.1 voltage-gated K⁺ (K_v) channels are present in the apical membranes of marginal cells of the stria vascularis of the inner ear, where they mediate K⁺ efflux into the scala media (cochlear duct) of the cochlea. As such, they are exposed to the K⁺-rich (∼150 mM of external K⁺ (K⁺_e)) environment of the endolymph. Previous studies have shown that K_v7.1 currents are substantially suppressed by high K⁺_e (independent of the effects of altering the electrochemical gradient). However, the molecular basis for this inhibition, which is believed to involve stabilization of an inactivated state, remains unclear. Using sequence alignment of S5-pore linkers of several K_v channels, we identified a key residue, E290, found in only a few K_v channels including K_v7.1. We used substituted cysteine accessibility methods and patch-clamp analysis to provide evidence that the ability of K_v7.1 to sense K⁺_e depends on E290, and that the charge at this position is essential for K_v7.1’s K⁺_e sensitivity. We propose that K_v7.1 may use this feedback mechanism to maintain the magnitude of the endocochlear potential, which boosts the driving force to generate the receptor potential of hair cells. The implications of our findings transcend the auditory system; mutations at this position also result in long QT syndrome in the heart.