Frampton DJA et al. (2022), Subtype-specific responses of hKv7.4 and hKv7.5...

XB-ART-59142

Elife 2022 Jun 01;11. doi: 10.7554/eLife.77672.

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

Frampton DJA , Choudhury K , Nikesjö J , Delemotte L , Liin SI .

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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.

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Species referenced: Xenopus laevis
Genes referenced: ctrl

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Figure 1. Docosahexaenoic acid facilitates the activation of hKV7.5 but inhibits the activation of hKV7.4. (A) Molecular structure of DHA. (B) Representative current family with corresponding G(V) curve of hKV7.5 in the absence (left) and presence (middle) of 70 µM DHA. Currents generated by the voltage protocol shown as inset. Red traces denote current generated by a test voltage to –40 mV. The G(V) curves (right) have been normalized between 0 and 1, as described in Materials and methods, to better visualize shifts in V50. Curves represent Boltzmann fits (see Materials and methods for details). V50 for this specific cell: V50,ctrl = –41.7 mV, V50,DHA = –59 mV. (C) Same as in B but for hKV7.4. Blue traces denote current generated by a test voltage to 0 mV. V50 for this specific cell: V50,ctrl = –12.6 mV, V50,DHA = –2.0 mV. (D–E) Concentration-response curve of the DHA effect on V50 of hKV7.5 (D) and hKV7.4 (E). Curves represent concentration-response fits (see Materials and methods for details). Best fits: ΔV50,max is –25.3 mV for hKV7.5 and +13.8 mV for hKV7.4. EC50 is 12 µM for hKV7.5 and 14 µM for hKV7.4. Data shown as mean ± SEM. n = 3–15. See also Figure 1—figure supplement 1, Figure 1—source data 1.

Figure 2. The DHA response has a rapid onset for both hKV7.5 and hKV7.4. Representative data showing wash-in and wash-out of 70 µM DHA on hKV7.5 (A) and hKV7.4 (B) for one oocyte each. Data points represent the current amplitude recorded following a test voltage to –40 mV (for hKV7.5) or +20 mV (for hKV7.4). The onset of DHA-induced activation of the hKV7.5 channel was quick, reaching a stable level of enhanced current within 5 min. Neither standard recording solution nor recording solution supplemented with BSA completely removed the DHA effect, and the enhanced current amplitude remained at almost threefold that of the baseline current amplitude. The onset of DHA-induced inhibition of the hKV7.4 channel was also quick, reaching a stable level of reduced current amplitude within 4.5 min. While not fully reversible, the DHA effect was reduced following re-perfusion with standard recording solution. Recording solution supplemented with 100 mg/mL BSA also reduced the inhibitory effect, with the current amplitude reaching approximately 89% of baseline current amplitude. Related to Figure 1.

References [+] :

AbuMweis, Eicosapentaenoic acid and docosahexaenoic acid containing supplements modulate risk factors for cardiovascular disease: a meta-analysis of randomised placebo-control human clinical trials. 2018, Pubmed