Subtype-specific responses of hKv7.4 and hKv7.5 channels to polyunsaturated fatty acids reveal an unconventional modulatory site and mechanism.

The K V 7.4 and K V 7.5 subtypes of voltage-gated potassium channels play a role in important physiological processes such as sound amplification in the cochlea and adjusting vascular smooth muscle tone. Therefore, the mechanisms that regulate K V 7.4 and K V 7.5 channel function are of interest. Here, we study the effect of polyunsaturated fatty acids (PUFAs) on human K V 7.4 and K V 7.5 channels expressed in Xenopus oocytes. We report that PUFAs facilitate activation of hK V 7.5 by shifting the V 50 of the conductance versus voltage (G(V)) curve toward more negative voltages. This response depends on the head group charge, as an uncharged PUFA analogue has no effect and a positively charged PUFA analogue induces positive V 50 shifts. In contrast, PUFAs inhibit activation of hK V 7.4 by shifting V 50 toward more positive voltages. No effect on V 50 of hK V 7.4 is observed by an uncharged or a positively charged PUFA analogue. Thus, the hK V 7.5 channel's response to PUFAs is analogous to the one previously observed in hK V 7.1-7.3 channels, whereas the hK V 7.4 channel response is opposite, revealing subtype-specific responses to PUFAs. We identify a unique inner PUFA interaction site in the voltage-sensing domain of hK V 7.4 underlying the PUFA response, revealing an unconventional mechanism of modulation of hK V 7.4 by PUFAs.