Polyunsaturated fatty acid analogues differentially affect cardiac Na_v, Ca_v, and K_v channels through unique mechanisms

Abstract

20The cardiac ventricular action potential depends on several voltage-gated ion channels, 21 including Nav, Cav, and Kv channels. Mutations in these channels can cause Long QT 22 Syndrome (LQTS) which increases the risk for ventricular fibrillation and sudden cardiac 23 death. Polyunsaturated fatty acids (PUFAs) have emerged as potential therapeutics for 24 LQTS because they are modulators of voltage-gated ion channels. Here we 25 demonstrate that PUFA analogues vary in their selectivity for human voltage-gated ion 26 channels involved in the ventricular action potential. The effects of specific PUFA 27 analogues range from selective for a specific ion channel to broadly modulating all three 28 cardiac ion channels (NaV, CaL, and IKs). In addition, PUFA analogues do not modulate 29 these channels through a shared mechanism. Our data suggest that different PUFA 30 analogues could be tailored towards specific forms of LQTS, which are caused by 31 mutations in distinct cardiac ion channels, and thus restore a normal ventricular action 32 potential. 34Polyunsaturated fatty acids (PUFAs) are amphipathic molecules that have been 82 suggested to possess antiarrhythmic effects (29, 30). PUFAs are characterized by 83 having a long hydrocarbon tail with two or more double bonds, as well as having a 84 charged, hydrophilic head group (31). PUFAs, such as DHA and EPA, have been 85 shown to prevent cardiac arrhythmias in animal models and cultured cardiomyocytes by 86 inhibiting the activity of Nav and Cav channels (30,(32)(33)(34). Specifically, DHA and EPA 87 are thought to bind to discrete sites on the channel protein to stabilize the inactivated 88 states of the Nav and Cav channels (32, 35). Since the voltage sensors of Nav and Cav 89 channels are relatively homologous, it has been suggested that PUFAs act on the 90 voltage-sensing S4 segments that control inactivation in these channels (30, 32). Our 91 group has demonstrated that PUFAs and PUFA analogues also modulate the activity of 92 the Kv7.1/KCNE1 channel and work to promote voltage-dependent activation of the IKs 93 current (36-38). The mechanism through which PUFAs promote Kv7.1/KCNE1 94 activation is referred to as the lipoelectric hypothesis which involves the following: 1) the 95 PUFA molecule integrates into the membrane via its hydrocarbon tail and 2) the 96 negatively charged PUFA head group electrostatically attracts the positively charged S4 97 segment and facilitates the outward movement of S4, promoting IKs channel activation 98 (36). Our group has also demonstrated that PUFAs and modified PUFAs exert a second 99 effect on the pore of Kv7.1 through an additional electrostatic interaction with a lysine 100 residue (K326) in the S6 segment (39). This electrostatic interaction between the 101 negatively charged PUFA head group and K326 leads to an increase in maximal 102 conductance of the channel (Gmax) (39).103 104 6Some groups have suggested that PUFAs could modify Nav channels by causing a 105 leftward shift in voltage dependent inactivation through...

Polyunsaturated fatty acid‐derived IKs channel activators shorten the QT interval ex‐vivo and in‐vivo

“…1f, Table I). The reason for the higher concentration of N-AT used in these experiments is that N-AT has an apparent lower affinity to the IKs channel compared with DHA-GLY and Lin-Gly 42 .…”

“…Xenopus oocytes, in addition to activating KCNQ1/KCNE1 channels 42 . Altogether, this suggests that natural and modified PUFAs shorten QT interval and APD in guinea pig hearts by targeting several ion channels.…”

Molecular mechanisms of modulation of KV7 channels by polyunsaturated fatty acids and their analogues

“…There is also a need to test the effect of PUFA analogs on physiological systems such as cardiomyocytes, neurons or whole hearts. In two recent papers the effect of PUFA analogs has been tested on NaV, CaV, cardiomyocytes and guinea pig hearts (Bohannon et al 2020a, Skarsfeldt et al 2020. Bohannon et al 2020 reported that the same PUFA analogs that can activate KV7.1 + E1 can inhibit NaV and CaV channels.…”

Structural determinants of Acid-sensing ion channel potentiation by single chain lipids

“…PUFAs have been shown to activate the large-conductance Ca 2+ -and voltage-gated K + (Slo1 BK) channel with a nanomolar EC50 (21)(22)(23). In addition, the voltage-gated potassium channel KV7.1 can be either potentiated or inhibited by PUFAs and PUFA derivatives depending on the nature of the lipid (24)(25)(26)(27)(28)(29)(30).…”

“…It has been suggested that dietary supplementation of ω-3 fatty acids can help patients with cystic fibrosis (40). In addition, PUFAs are being designed as a potential treatment for patients with Long QT syndrome type 1 (24,27,29,30). ASICs are potentially interesting targets for the inhibition of pain and the inhibition of cell death in both ischemia and neurodegenerative disorders.…”