Liin SI , Silverå Ejneby M , Barro-Soria R , Skarsfeldt MA , Larsson JE , Starck Härlin F , Parkkari T , Bentzen BH , Schmitt N , Larsson HP , Elinder F .

R01 GM109762 NIGMS NIH HHS , R01GM109762 NIGMS NIH HHS

	Fig. 1. DHA shifts the voltage dependence of Kv7.1. (A) DHA (70 μM) increases current amplitude of Kv7.1 in response to a −20-mV voltage step. (B) DHA (70 μM) shifts the G(V) of Kv7.1. DHA (●), control (○). Dashed curve in B is control curve shifted −10 mV. (C) Concentration dependence of DHA effect. Mean ± SEM. δVmax = −15.8 mV, c0.5 = 50 μM. n = 3–5.
	Fig. 2. A charged head group and a polyunsaturated acyl tail are necessary. (A) Induced G(V) shifts for 70 μM of indicated substance. Means ± SEM n = 3–8. (B) pH dependence of the G(V) shift caused by the application of 70 µM DHA on Kv7.1. Means ± SEM. δVmax = −28.0 mV, c0.5 = 1.8 × 10−8 = pH 7.7. n = 3–5. (C) Concentration-response curves for DHA on Kv7.1 at different pHs. pH 9.0: δVmax = −27.7 mV, c0.5 = 10 μM; pH 7.4, see Fig. 1C. n = 3–8. (D) Schematic illustration of PUFA modulation. PUFAs incorporate in the lipid cleft close to the channel’s VSD and electrostatically affect the S4 movement. +++, S4 gating charges.
	Fig. 3. KCNE1 abolishes PUFA effect on Kv7.1/KCNE1 at physiological pH. (A–D) DHA (70 μM) applied on Kv7.1/KCNE1 at pH 7.4 (A and B) and pH 9 (C and D). DHA (●), control (○). Bold traces = 0 mV (A) or +10 mV (C). Dashed curve in D is control curve shifted −35 mV. (E) pH dependence for 70 µM DHA. Kv7.1/KCNE1: δVmax = −29.0 mV, c0.5 = 2.5 × 10−9 = pH 8.6. n = 3–6. For Kv7.1, see Fig. 2B. (F) Model: KCNE1 changes probability of protonation of negatively charged acidic (Upper) and positively charged amine (Lower) PUFA analogs, thereby changing PUFA-Kv7.1 voltage sensor (+++) interactions. (G) G(V) shift induced by 70 µM DHA or AA+. n = 3–8.
	Fig. 4. PUFA analogs are effective on Kv7.1/KCNE1. (A) DHA-Gly (70 μM) induces a negative G(V) shift of Kv7.1/KCNE1. DHA-Gly (●), control (○). Dashed line is control curve shifted −20 mV. (B) pH dependence for 70 µM DHA-Gly or 70 µM DHA applied on Kv7.1/KCNE1. DHA-Gly: δVmax = −38.8 mV, c0.5 = 7.6 × 10−8 = pH 7.1. n = 3–6. For DHA, see Fig. 3E. (C) N-arachidonoyl taurine (N-AT; 70 µM) induces a negative G(V) shift of Kv7.1/KCNE1. N-AT (●), control (○). Dashed line is control curve shifted −24 mV. (D) DHA-Gly (70 µM) does not shift Kv7.1/R228Q and has a smaller effect on Kv7.1/K218C and Kv7.1/G219C. Means ± SEM; n = 4–14. (E) Normalized fluorescence during an activating test pulse to −60 mV from a holding voltage of −120 mV. (F) N-AT (70 μM) shifts the F(V) of Kv7.1/G219C*. N-AT (●), control (○).The continuous lines are Boltzmann curves (Eq. 1) fitted to experimental data. For control: V50 = −41.1 mV; s = 11.7. For N-AT: V50 = −61.1 mV; s = 16.3. Means ± SEM; n = 9.
	Fig. 5. Antiarrhythmic effect of PUFA analogs. (A and B) Effect of 30 µM N-AT on action potential duration and frequency in isolated embryonic rat cardiomyocytes. (C) Example of the effect of 30 µM N-AT on current amplitude in isolated embryonic rat cardiomyocytes. Gray trace is current in control solution from a voltage 20 mV more positive than the N-AT trace. (D–F) Representative examples of arrhythmia induced by application of 5 µM Chromanol 293B or 5 µM Chromanol 293B + 30 µM N-arachidonoyl taurine (N-AT) in isolated embryonic rat cardiomyocytes. (G and H) Representative example of effect of 0.03 µM E4031 and 10 µM DHA-Gly on QT interval (G) and action potential duration (H) in isolated perfused guinea pig heart. Hearts are paced at 250 beats/min. (I) Summary of effect of 0.03 µM E4031 and 10 µM DHA-Gly on QT interval and action potential duration (APD90) in isolated perfused guinea pig heart. Means ± SEM; n =3. Statistical significance compared with control.

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