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

Abstract

Polyunsaturated fatty acids with double bonds closer to the head group had higher apparent affinity for I channels and increased I current more; shifting the bonds further away from the head group reduced apparent binding affinity for and effects on the I 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 channels in Long QT Syndrome.

Polyunsaturated Fatty Acids as Modulators of KV7 Channels

“…The first indication of this came from studies by Doolan et al (2002) and Moreno et al (2015) both of which show DHA induces overall greater effects on K V 7.1/KCNE1 than EPA does. This is in agreement with our comparison of 16 PUFAs with different tail properties, in which we find that PUFAs with double bonds proximal to the head-group have a higher apparent affinity to K V 7.1/KCNE1, compared with PUFAs with more distal double bonds (Bohannon et al, 2019). In contrast, there was either no or weak correlation between tail length or number of double tail bonds and K V 7.1/KCNE1 effects (Bohannon et al, 2019).…”

“…We find that a negatively charged PUFA head-group is critical to the shift in V 50 of K V 7.1 and K V 7.2/7.3 toward negative voltages. Fully deprotonated PUFAs (promoted by an alkaline extracellular solution) cause larger negative V 50 shifts (Liin et al, 2015;Larsson et al, 2018;Bohannon et al, 2019). Protonated PUFAs and uncharged PUFA analogs (PUFA methyl esters) are unable to shift V 50 (Liin et al, 2015(Liin et al, , 2016a.…”

Alpha and omega in potassium‐channel opening

“…In this issue of Acta Physiologica , a study from the laboratory of Peter Larsson shows that the distance between the carboxyl group and the first double bond of polyunsaturated fatty acids (PUFAs) is critical for the affinity of the PUFA molecule to a voltage‐gated potassium channel found in the heart . A shorter distance increases the affinity, and the bound PUFA alters the channel's voltage dependence and thereby opens the channel.…”

“…Now Bohannon et al . has challenged this view and systematically explored 16 different PUFAs on the slowly activating potassium ( I Ks ) channel, which is important for the repolarization of the cardiac action potential, expressed in Xenopus oocytes.…”

“…However, the ω distance plays a role for the efficacy of PUFAs on V 0.5 ; a longer ω distance increases the shift in the channel's voltage dependence. This might explain why ω −6 but not ω −3 PUFAs decrease the risk of cardiovascular disease and death …”