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 IK s potassium channel.
AIM
The IK s channel is important for termination of the cardiac action potential. Hundreds of loss-of-function mutations in the IK 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 IK s channels. However, it is unclear which properties of PUFAs are essential for their effects on IK s channels.


METHODS
To understand how PUFAs influence IK s channel activity, we measured effects on IK 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 IK s channels. However, we found a strong correlation between the positions of the double bonds relative to the head group and effects on IK s channels.


CONCLUSION
Polyunsaturated fatty acids with double bonds closer to the head group had higher apparent affinity for IK s channels and increased IK s current more; shifting the bonds further away from the head group reduced apparent binding affinity for and effects on the IK 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 IK s channels in Long QT Syndrome.
['Bohannon|Briana M|BM|0000-0002-3720-1477', 'Perez|Marta E|ME|', 'Liin|Sara I|SI|0000-0001-8493-0114', 'Larsson|Hans Peter|HP|0000-0002-1688-2525']
D000200:Action Potentials D000818:Animals D002478:Cells, Cultured D043371:Fatty Acids, Omega-6 D005231:Fatty Acids, Unsaturated D006801:Humans D051657:KCNQ1 Potassium Channel D009865:Oocytes D024642:Potassium Channels, Voltage-Gated D014982:Xenopus laevis
polyunsaturated fatty acids Long QT Syndrome I
K

s KCNE1 KCNQ1 Kv7.1