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_{K s} potassium channel

Aim: The I_{K s} channel is important for termination of the cardiac action potential. Hundreds of loss-of-function mutations in the I_{K s} 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_{K s} channels. However, it is unclear which properties of PUFAs are essential for their effects on I_{K s} channels. Methods: To understand how PUFAs influence I_{K s} channel activity, we measured effects on I_{K s} 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_{K s} channels. However, we found a strong correlation between the positions of the double bonds relative to the head group and effects on I_{K s} channels. Conclusion: Polyunsaturated fatty acids with double bonds closer to the head group had higher apparent affinity for I_{K s} channels and increased I_{K s} current more; shifting the bonds further away from the head group reduced apparent binding affinity for and effects on the I_{K s} 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_{K s} channels in Long QT Syndrome.