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.