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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
Author(s) -
Bohan Briana M.,
Perez Marta E.,
Liin Sara I.,
Larsson Hans Peter
Publication year - 2019
Publication title -
acta physiologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.591
H-Index - 116
eISSN - 1748-1716
pISSN - 1748-1708
DOI - 10.1111/apha.13186
Subject(s) - polyunsaturated fatty acid , chemistry , double bond , short qt syndrome , torsades de pointes , repolarization , stereochemistry , long qt syndrome , fatty acid , electrophysiology , medicine , biochemistry , qt interval , organic chemistry
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 ( PUFA s) are potential therapeutics for Long QT Syndrome, as they affect I K s channels. However, it is unclear which properties of PUFA s are essential for their effects on I K s channels. Methods To understand how PUFA s 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 PUFA s, 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.