Abstract
The cardiac ventricular action potential depends on several voltage-gated ion channels, including NaV, CaV, and KV channels. Mutations in these channels can cause Long QT Syndrome (LQTS) which increases the risk for ventricular fibrillation and sudden cardiac death. Polyunsaturated fatty acids (PUFAs) have emerged as potential therapeutics for LQTS because they are modulators of voltage-gated ion channels. Here we demonstrate that PUFA analogues vary in their selectivity for human voltage-gated ion channels involved in the ventricular action potential. The effects of specific PUFA analogues range from selective for a specific ion channel to broadly modulating cardiac ion channels from all three families (NaV, CaV, and KV). In addition, a PUFA analogue selective for the cardiac IKs channel (Kv7.1/KCNE1) is effective in shortening the cardiac action potential in human-induced pluripotent stem cell-derived cardiomyocytes. Our data suggest that PUFA analogues could potentially be developed as therapeutics for LQTS and cardiac arrhythmia.
Highlights
The human ventricular action potential is mediated by the coordinated activity of several different voltage-dependent ion channels (Mohrman and Heller, 2010)
To compare the effects of different Polyunsaturated fatty acids (PUFAs) analogues on these three different channels, we here measure the currents from Kv7.1/KCNE1, Cav1.2/b3/a2d, and Nav1.5/b1 expressed in Xenopus oocytes using two-electrode voltage clamp
We have previously shown that PUFAs promote the activation of Kv7.1/KCNE1 channels through the lipoelectric mechanism where the negatively charged PUFA head group electrostatically attracts both the S4 voltage sensor and K326 in S6 (Borjesson et al, 2008; Liin et al, 2018a; Borjesson and Elinder, 2011)
Summary
The human ventricular action potential is mediated by the coordinated activity of several different voltage-dependent ion channels (Mohrman and Heller, 2010). The rapid upstroke of the ventricular action potential is mediated by the activation of the voltage-gated Na+ channel, Nav1.5, which rapidly inactivates. Inactivation of Cav1.2 channels along with the activation of the slow delayed-rectifier K+ channels, Kv11.1 (which generates the IKr current) and Kv7.1/KCNE1 (which generates the IKs current), work to promote repolarization of the cell membrane together with the IK1 current (Nerbonne and Kass, 2005) Mutations of these ion channels (or channelopathies) could lead to Long QT Syndrome (LQTS), which is an arrhythmogenic disorder that predisposes the individual to potentially fatal cardiac arrhythmias (Alders and Christiaans, 2003; Bohnen et al, 2017)
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