The KV7.4 and KV7.5 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 KV7.4 and KV7.5 channel function are of interest. Here, we study the effect of polyunsaturated fatty acids (PUFAs) on human KV7.4 and KV7.5 channels expressed in Xenopus oocytes. We report that PUFAs facilitate activation of hKV7.5 by shifting the V50 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 V50 shifts. In contrast, PUFAs inhibit activation of hKV7.4 by shifting V50 toward more positive voltages. No effect on V50 of hKV7.4 is observed by an uncharged or a positively charged PUFA analogue. Thus, the hKV7.5 channel's response to PUFAs is analogous to the one previously observed in hKV7.1-7.3 channels, whereas the hKV7.4 channel response is opposite, revealing subtype-specific responses to PUFAs. We identify a unique inner PUFA interaction site in the voltage-sensing domain of hKV7.4 underlying the PUFA response, revealing an unconventional mechanism of modulation of hKV7.4 by PUFAs.
Keywords: KCNQ; cell biology; docosahexaenoic acid; electrophysiology; lipid; molecular biophysics; molecular dynamics simulations; omega 3; structural biology; xenopus.
In order to carry out their roles in the body, cells need to send and receive electrical signals. They can do this by allowing ions to move in and out through dedicated pore-like structures studded through their membrane. These channels are specific to one type of ions, and their activity – whether they open or close – is carefully controlled. In humans, defective ion channels are associated with conditions such as irregular heartbeats, epileptic seizures or hearing loss. Research has identified molecules known as polyunsaturated fatty acids as being able to control the activity of certain members of the KV7 family of potassium ion channels. The KV7.1 and KV7.2/7.3 channels are respectively present in the heart and the brain; KV7.4 is important for hearing, while KV7.5 plays a key role in regulating muscle tone in blood vessels. Polyunsaturated fatty acids can activate KV7.1 and KV7.2/7.3 but their impact on KV7.4 and KV7.5 remains unclear. Frampton et al. explored this question by studying human KV7.4 and KV7.5 channels expressed in frog egg cells. This showed that fatty acids activated KV7.5 (as for KV7.1 and KV7.2/7.3), but that they reduced the activity of KV7.4. Closely examining the structure of KV7.4 revealed that the fatty acids were binding to a different region compared to the other KV7 channels. When this site was made inaccessible, fatty acids increased the activity of KV7.4, just as for the rest of the family. These results may help to understand the role of polyunsaturated fatty acids in the body. In addition, knowing how these molecules interact with channels in the same family will be useful for optimising a drug’s structure to avoid side effects. However, further research will be needed to understand the broader impact in a more complex biological organism.
© 2022, Frampton et al.