Liin, S. I. | Search bioRxiv

bioRxiv2021

Subtype specific responses in hKv7.4 and hKv7.5 channels to polyunsaturated fatty acids

The KV7.4 and KV7.5 subtypes of voltage-gated potassium channels are expressed in several tissues where they play a role in 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 KV7.5 is activated by PUFAs, which shift the V50 of the conductance versus voltage (G(V)) curve towards more negative voltages. This response depends on the charge of the head group as an uncharged PUFA analogue has no effect and a positively charged PUFA analogue induces positive V50 shifts. In contrast, we find that the KV7.4 channel is inhibited by PUFAs, which shift V50 towards more positive voltages. No effect on V50 of KV7.4 is observed by an uncharged or a positively charged PUFA analogue. Oocytes co-expressing KV7.4 and KV7.5 display an intermediate response to PUFAs. Altogether, the KV7.5 channels response to PUFAs is like that previously observed in KV7.1-7.3 channels, whereas the KV7.4 channel response is opposite, revealing subtype specific responses to PUFAs.

biophysics↗

bioRxiv2019

Polyunsaturated fatty acid analogues differentially affect cardiac Nav, Cav, and Kv channels through unique mechanisms

The cardiac ventricular action potential depends on several voltage-gated ion channels, including Nav, Cav, and Kv channels. Mutations in these channels can cause Long QT Syndrome (LQTS) which increases the risk for ventricular fibrillation and sudden cardiac death. Polyunsaturated fatty acids (PUFAs) have emerged as potential therapeutics for LQTS because they are modulators of voltage-gated ion channels. Here we demonstrate that PUFA analogues vary in their selectivity for human voltage-gated ion channels involved in the ventricular action potential. The effects of specific PUFA analogues range from selective for a specific ion channel to broadly modulating all three cardiac ion channels (NaV, CaL, and IKs). In addition, PUFA analogues do not modulate these channels through a shared mechanism. Our data suggest that different PUFA analogues could be tailored towards specific forms of LQTS, which are caused by mutations in distinct cardiac ion channels, and thus restore a normal ventricular action potential.

biophysics↗