Regulation of the voltage-gated potassium channel KCNQ4 in the auditory pathway
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The potassium channel KCNQ4, expressed in the mammalian cochlea, has been associated tentatively with an outer hair cell (OHC) potassium current, IK,n, a current distinguished by an activation curve shifted to exceptionally negative potentials. Using CHO cells as a mammalian expression system, we have examined the properties of KCNQ4 channels under different phosphorylation conditions. The expressed current showed the typical KCNQ4 voltage-dependence, with a voltage for half-maximal activation (V1/2) of −25 mV, and was blocked almost completely by 200 µM linopirdine. Application of 8-bromo-cAMP or the catalytic sub-unit of PKA shifted V1/2 by approximately −10 and −20 mV, respectively. Co-expression of KCNQ4 and prestin, the OHC motor protein, altered the voltage activation by a further −15 mV. Currents recorded with less than 1 nM Ca2+ in the pipette ran down slowly (12% over 5 min). Buffering the pipette Ca2+ to 100 nM increased the run-down rate sevenfold. Exogenous PKA in the pipette prevented the effect of elevated [Ca2+]i on run-down. Inhibition of the calcium binding proteins calmodulin or calcineurin by W-7 or cyclosporin A, respectively, also prevented the calcium-dependent rapid run-down. We suggest that KCNQ4 phosphorylation via PKA and coupling to a complex that may include prestin can lead to the negative activation and the negative resting potential found in adult OHCs.