ω-6 and ω-9 polyunsaturated fatty acids with double bonds near the carboxyl head have the highest affinity and largest effects on the cardiac I_Ks potassium channel

Aim: The I_Ks channel is important for termination of the cardiac action potential. Hundreds of loss-of-function mutations in the I_Ks channel reduce the K⁺ current and, thereby, delay the repolarization of the action potential, causing Long QT Syndrome. Long QT predisposes individuals to Torsades de Pointes which can lead to ventricular fibrillation and sudden death. Polyunsaturated fatty acids (PUFAs) are potential therapeutics for Long QT Syndrome, as they affect I_Ks channels. However, it is unclear which properties of PUFAs are essential for their effects on I_Ks channels. Methods: To understand how PUFAs influence I_Ks channel activity, we measured effects on I_Ks current by two-electrode voltage clamp while changing different properties of the hydrocarbon tail. Results: There was no, or weak, correlation between the tail length or number of double bonds in the tail and the effects on or apparent binding affinity for I_Ks channels. However, we found a strong correlation between the positions of the double bonds relative to the head group and effects on I_Ks channels. Conclusion: Polyunsaturated fatty acids with double bonds closer to the head group had higher apparent affinity for I_Ks channels and increased I_Ks current more; shifting the bonds further away from the head group reduced apparent binding affinity for and effects on the I_Ks current. Interestingly, we found that ω-6 and ω-9 PUFAs, with the first double bond closer to the head group, left-shifted the voltage dependence of activation the most. These results allow for informed design of new therapeutics targeting I_Ks channels in Long QT Syndrome.