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

The K7.4 and K7.5 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 K7.4 and K7.5 channel function are of interest. Here, we study the effect of polyunsaturated fatty acids (PUFAs) on human K7.4 and K7.5 channels expressed in oocytes. We report that PUFAs facilitate activation of hK7.5 by shifting the V of the conductance 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 shifts. In contrast, PUFAs inhibit activation of hK7.4 by shifting V toward more positive voltages. No effect on V of hK7.4 is observed by an uncharged or a positively charged PUFA analogue. Thus, the hK7.5 channel's response to PUFAs is analogous to the one previously observed in hK7.1-7.3 channels, whereas the hK7.4 channel response is opposite, revealing subtype-specific responses to PUFAs. We identify a unique inner PUFA interaction site in the voltage-sensing domain of hK7.4 underlying the PUFA response, revealing an unconventional mechanism of modulation of hK7.4 by PUFAs.