The human ventricular action potential is mediated by the coordinated activity of several different voltage-dependent ion channels (Mohrman and Heller, 2010). The ventricular myocyte is hyperpolarized during diastole between two action potentials mainly due to inward rectifier I_K1 K⁺ channels. The ventricular action potential spreads between cardiomyocytes by currents through gap junction channels. The rapid upstroke of the ventricular action potential is mediated by the activation of the voltage-gated Na⁺ channel, Nav1.5, which then rapidly inactivates. This is followed by the activation and inactivation of the voltage-gated I_to K⁺ channels. The activation of L-type voltage gated Ca²⁺ channels, Cav1.2, and influx of Ca²⁺ leads to a sustained depolarization, or plateau phase, and the contraction of the cardiac muscle. Inactivation of Cav1.2 channels along with the activation of the slow delayed-rectifier K⁺ channels, Kv11.1 (which generates the I_Kr current) and Kv7.1/KCNE1 (which generates the I_Ks current), work to promote repolarization of the cell membrane together with the I_K1 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). We will here focus on the effects of PUFA analogues on Nav1.5, Cav1.2, and Kv7.1 together with some of their associated subunits to try to assess the effects of PUFA analogues on the currents through these channels on the ventricular action potential.

The Nav1.5 α-subunit contains four non-identical linked domains, domains I-4 (DI-DIV). Each of these domains contain 6 transmembrane segments (S1-S6), where the S1-S4 segments make up the voltage-sensing domains (VSD) and S5-S6 segments make up the pore domains (PD). The S4 helix of each of the four domains contains a motif with positively charged amino acid residues which allow the S4 segment to detect and respond to changes in the membrane electric field, acting as the channel voltage sensor (Chanda and Bezanilla, 2002). The movement of these voltage sensors determines the voltage dependence of activation and inactivation, where activation of the DI-III S4s are suggested to promote channel activation and activation of DIV S4 segment is sufficient to induce voltage-dependent inactivation of Nav1.5 (Capes et al., 2013). The Nav1.5 α-subunit exists as a macromolecular complex with the accessory subunit β1. β1 is a single transmembrane spanning helix that modifies the kinetics of Nav1.5 channel activation and inactivation and can alter the pharmacology of the Nav1.5 α-subunit (Barro-Soria et al., 2017; Xiao et al., 2000; Zhu et al., 2017). Gain-of-function mutations of Nav1.5 increase Na⁺ currents and lead to LQTS Type 3 (LQT3) (Fernández-Falgueras et al., 2017; Calloe et al., 2013; Rivolta et al., 2002).

Like Nav1.5, the Cav1.2 α-subunit contains four linked domains, DI-DIV, where each domain consists of 6 transmembrane segments S1-S6. S1-S4 form the VSD, where S4 acts as the voltage sensor, and S5-S6 form the PD. Cav1.2 exists as a large macromolecular complex with the accessory subunits β3 and α2δ subunits that are important for membrane expression and alter channel activation and deactivation kinetics, respectively (Rougier and Abriel, 1863; Chen et al., 2004). Cav1.2/β3/α2δ undergoes both voltage-dependent inactivation and calcium-dependent inactivation (Stotz et al., 2004; Zhang et al., 1994) which allows it to regulate Ca²⁺ influx into the cardiomyocyte. Gain-of-function mutations of Cav1.2 increase Ca²⁺ currents and lead to LQT Type 8 (LQT8) (Dick et al., 2016; Hoffman, 1995).

The voltage-gated K⁺ channel, Kv7.1, along with the auxiliary subunit KCNE1, mediates an important repolarizing K⁺ current, I_Ks (Noble and Tsien, 1969; Deal et al., 1996; Lei and Brown, 1996). The Kv7.1 α-subunit contains 6 transmembrane segments, S1-S6. S1-S4 comprise the VSD, where S4 contains several positively charged amino acid residues that allow S4 to act as the voltage sensor of Kv7.1. S5-S6 segments comprise the channel PD. Kv7.1 forms a tetrameric channel, where 4 Kv7.1 α-subunits arrange to form a functional channel. The auxiliary β-subunit KCNE1 drastically modulates Kv7.1 channel voltage dependence, activation kinetics, and single-channel conductance (Barro-Soria et al., 2014; Osteen et al., 2010). Loss-of-function mutations in the Kv7.1 α-subunit and KCNE1 β-subunit lead to reductions in I_Ks and can lead to LQTS Type 1 (LQT1) and Type 5 (LQT5) (Huang et al., 2018; Ma et al., 2015; Schwartz et al., 2012; Sanguinetti, 1999; Harmer et al., 2010), respectively.

Polyunsaturated fatty acids (PUFAs) are amphipathic molecules that have been suggested to possess antiarrhythmic effects (Endo and Arita, 2016; Kang and Leaf, 2000). PUFAs are characterized by having a long hydrocarbon tail with two or more double bonds, as well as having a charged, hydrophilic head group (Benatti et al., 2004). PUFAs, such as DHA and EPA, have been shown to prevent cardiac arrhythmias in animal models and cultured cardiomyocytes by inhibiting the activity of Na_V and Ca_V channels (Kang and Leaf, 2000; Kang and Leaf, 1996; Xiao et al., 1997; Xiao et al., 1995). Specifically, DHA and EPA are thought to bind to discrete sites on the channel protein to stabilize the inactivated states of the Na_V and Ca_V channels (Kang and Leaf, 1996; Xiao et al., 2001). Since the voltage sensors of Na_V and Ca_V channels are relatively homologous, it has been suggested that PUFAs act on the voltage-sensing S4 segments that control inactivation in these channels (Kang and Leaf, 2000; Kang and Leaf, 1996). Our group has demonstrated that PUFAs and PUFA analogues also modulate the activity of the Kv7.1/KCNE1 channel and work to promote voltage-dependent activation of the I_Ks current (Börjesson et al., 2008; Liin et al., 2015; Liin et al., 2016). The mechanism through which PUFAs promote Kv7.1/KCNE1 activation is referred to as the lipoelectric hypothesis which involves the following: 1) the PUFA molecule integrates into the membrane via its hydrocarbon tail and 2) the negatively charged PUFA head group electrostatically attracts the positively charged S4 segment and facilitates the outward movement of S4, promoting Kv7.1/KCNE1 channel activation (Börjesson et al., 2008; Bohannon et al., 2020). Our group has also demonstrated that PUFAs and modified PUFAs exert a second effect on the pore of Kv7.1 through an additional electrostatic interaction with a lysine residue (K326) in the S6 segment (Liin et al., 2018a). This electrostatic interaction between the negatively charged PUFA head group and K326 leads to an increase in maximal conductance of the channel (Liin et al., 2018a). In addition, previous investigation of the anti-arrhythmic potential of PUFA analogues have shown that the negatively charged PUFA analogues are able to shorten a pharmacologically prolonged ventricular action potential and QT interval in isolated guinea pig hearts (Liin et al., 2015).

In previous experiments, it was discovered that activation of Kv7.1 by DHA is abolished when Kv7.1 is co-expressed with the auxiliary subunit KCNE1, which is necessary for the physiological I_Ks current (Liin et al., 2015). However, PUFA-induced activation of the cardiac Kv7.1/KCNE1 channel can be restored by conducting experiments using DHA at pH 9 (Liin et al., 2015). Recent work has demonstrated that KCNE1 induces a conformational change in Kv7.1 that bring acidic residues (namely E290) closer to the PUFA binding site, leading to protonation of the PUFA head group (Larsson et al., 2018). The deprotonated, negatively charged head group is necessary for PUFA-induced activation of the Kv7.1/KCNE1 channel. Therefore it is necessary to use modified PUFAs that are deprotonated at physiological pH (7.5) (Liin et al., 2015). We found that the PUFA analogues N-arachidonoyl taurine (N-AT) and docosahexaenoyl glycine (DHA-glycine) have head groups with a lower pKa, allowing these analogues to remain negatively charged at physiological pH and activate the Kv7.1/KCNE1 channel (Liin et al., 2015; Liin et al., 2016; Bohannon et al., 2020).

Some groups have suggested that PUFAs could modify Na_V channels by causing a leftward shift in voltage dependent inactivation through an electrostatic effect on the voltage-sensing domains involved in inactivation (Kang and Leaf, 2000; Kang and Leaf, 1996). It is possible that PUFAs modulate Kv7.1/KCNE1, Nav1.5/β1, and Cav1.2/β3/α2δ channels by a similar mechanism by integrating next to the S4 voltage sensors and electrostatically attracting the voltage sensors toward their outward position. If PUFAs integrate preferentially next to the S4 that controls inactivation in Nav1.5/β1 and Cav1.2/β3/α2δ channels but next to all S4s in Kv7.1/KCNE1 channels, PUFAs would promote activation in Kv7.1/KCNE1 channels but promote inactivation in Nav1.5/β1 and Cav1.2/β3/α2δ channels. Though both PUFAs and PUFA analogues are known to modulate different ion channel activities (i.e. processes underlying activation and inactivation), it is unclear whether specific PUFAs and PUFA analogues are selective for certain ion channels or if they broadly influence the activity of several different ion channels simultaneously. PUFAs would provide an alternative to the current treatments used for LQTS. Current treatments include prescription of beta blockers or an implantable cardioverter defibrillator as means of preventing arrhythmia. However, these treatments do not target the underlying cause of LQTS, which is mutations in voltage-gated ion channels expressed in cardiomyocytes. In addition, there are some cases of LQTS where patients are resistant to current treatments (Chockalingam et al., 2012; Waddell-Smith and Skinner, 2016). PUFA analogues, however, have the potential to specifically target the ion channels that are implicated in LQTS and may benefit patients who have resistant forms of LQTS.

In this work, we characterize the channel-specific effects of different PUFAs and PUFA analogues in order to further understand which PUFAs and PUFA analogues would be the most therapeutically relevant in the treatment for different LQTS subtypes. We have found that PUFA analogues modulate Kv7.1/KCNE1, Cav1.2/β3/α2δ, and Nav1.5/β1 through different mechanisms instead of through a shared mechanism. In addition, we demonstrate that PUFA analogues exhibit a broad range of differences in selectivity for Kv7.1/KCNE1, Cav1.2/β3/α2δ, and Nav1.5/β1. PUFA analogues that are more selective for Kv7.1/KCNE1 are able to restore a prolonged ventricular action potential and prevent arrhythmia in simulated cardiomyocytes. Finally, PUFA analogues that are selective for Kv7.1/KCNE1 are able to shorten the ventricular action potential in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).

We show here that PUFA analogues have different mechanisms of action on Kv7.1/KCNE1, Cav1.2/β3/α2δ, and Nav1.5/β1 channels. 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 (facilitating its upward movement and channel opening) and K326 in S6 (increasing the maximal conductance) (Börjesson et al., 2008; Liin et al., 2018a; Börjesson and Elinder, 2011). In both Cav1.2/β3/α2δ and Nav1.5/β1 channels, PUFAs and PUFA analogues inhibit channel currents. We have found that PUFA analogues cause a dose-dependent reduction in the currents through Cav1.2/β3/α2δ channels. Surprisingly this inhibition occurs with no effect on the voltage dependence of either activation or inactivation. In Nav1.5/β1 channels, PUFA analogues cause inhibition through a dose-dependent decrease in currents, with both a left-shifting effect on the voltage dependence of inactivation and a decrease in conductance. We also demonstrate that PUFA analogues vary in their selectivity for voltage-gated ion channels. The selectivity depends on the specific concentration of PUFA analogues applied, because several compounds have non-overlapping dose response curves for their effects on the three different channels (Figure 6). We also found that PUFA analogues with taurine head groups tend to have broad modulatory effects on Kv7.1/KCNE1, Nav1.5/β1 and Cav1.2/β3/α2δ channels, generally displaying higher apparent affinity for Cav1.2/β3/α2δ and Nav1.5/β1 channels. Conversely, PUFA analogues with glycine head groups tend to be more selective for Kv7.1/KCNE1 channels and display lower apparent affinity for Cav1.2/β3/α2δ and Nav1.5/β1 channels. By understanding the effects of PUFA analogues on individual channels, it opens up the possibility to target specific forms of LQTS in which specific channels are mutated.

In this work, we have demonstrated that PUFA analogues modulate several different voltage-gated ion channels, including some underlying the ventricular action potential: Kv7.1/KCNE1, Nav1.5/β1, and Cav1.2/β3/α2δ. The PUFA analogue-induced increases in current seen for Kv7.1/KCNE1 would tend to shorten the AP duration. We have previously shown that a PUFA analogue that increases I_Ks currents shortens the AP duration and has anti-arrhythmic effects in rat cardiomyocytes (Liin et al., 2016). Work in animals has shown that PUFAs such as DHA and EPA are effective in terminating arrhythmia (Kang and Leaf, 2000). These anti-arrhythmic effects were proposed to occur through PUFA-mediated inhibition of Na_V and Ca_V channels, leading us to believe that PUFA analogue-induced inhibition of Cav1.2/β3/α2δ, and late Nav1.5/β1 currents would also tend to shorten the AP duration and potentially be anti-arrhythmic (Kang and Leaf, 2000; Kang and Leaf, 1996; Xiao et al., 1997; Xiao et al., 1995). Therefore, all of these effects could potentially be beneficial for patients with Long QT Syndrome. In the case of I_Ks (Kv7.1/KCNE1) currents, PUFA analogues would rescue loss-of-function mutants of Kv7.1/KCNE1 (I_Ks) channels in LQT1 (KCNQ1 mutations) or LQT5 (KCNE1 mutations). In the case of Na_V and Ca_V currents, PUFAs would inhibit gain-of-function mutants of Nav1.5/β1 and Cav1.2/β3/α2δ channels in LQT3 or LQT8, respectively. In LQT3, it is increases in the late Na_V currents that cause the prolonged APD. It is difficult to measure late Nav1.5/β1 currents in whole oocyte experiments. However, the PUFA-induced left-shifts in the voltage dependence of inactivation and decreases in the maximal conductance observed in our measured Nav1.5/β1 currents are assumed to also result in decreased Nav1.5/β1 late currents. There are several other currents, such as the I_Kr, that contribute to the ventricular action potential that we have not assessed here for potential PUFA effects. However, neither N-AT nor DHA-glycine up to 10 μM had any significant effects on currents through Herg channels (that together with the β subunit KCNE2 form the I_Kr channels) expressed in heterologous systems (B.H. Bentzen and H. Duff, unpublished data).

Whether all these effects on these different ion channels are all anti-arrhythmic would have to be tested further in future in vitro and in vivo studies. However, to assess the potential for therapeutic effects of PUFA analogues on the cardiac action potential, we used the O’Hara-Rudy Dynamic (ORd) model in MATLAB to simulate the ventricular action potential in the presence of different PUFA analogues. In our simulations, PUFA analogues that are non-selective (i.e. that activate Kv7.1/KCNE1 while inhibiting Cav1.2/β3/α2δ and Nav1.5/β1) prevent the generation of an action potential. However, when we simulate the effects of Pin-glycine and DHA-glycine, which are both more selective for Kv7.1/KCNE1, we see a shortening in the action potential duration and the suppression of early afterdepolarizations. This suggests that selectively boosting I_Ks (Kv7.1/KCNE1) current would be important for shortening and terminating the ventricular action potential. To further probe the therapeutic potential of PUFA analogues, we applied DHA-glycine to hiPSC-derived cardiomyocytes and found that DHA-glycine shortens the duration of the ventricular action potential. The next step in evaluating the therapeutic potential of PUFA analogues would be applying PUFA analogues to hiPSC-derived cardiomyocytes from patients bearing LQTS-causing mutations.

In our experiments using PUFA analogues on Nav1.5/β1, we observed both a shift in the voltage dependence of inactivation and a dose-dependent decrease in Na⁺ currents. Extensive work has been done to characterize how each of the different voltage-sensing domains in Na_V channels contribute to voltage-dependent activation and inactivation, many implicating DIV S4 in fast inactivation (Capes et al., 2013; Ahern et al., 2015). Recent work by Hsu et al. (2017) has also shown using voltage clamp fluorometry, the importance of both DIII and DIV in Na_V channel inactivation (Hsu et al., 2017). Our data suggest that PUFA analogues may interact with S4 segments involved in voltage-dependent inactivation, allowing PUFA analogues to left-shift the voltage dependence of inactivation. However, this does not completely explain the additional dose-dependent decrease in Na⁺ currents we observe on top of the leftward shifted voltage dependence of inactivation. Recent work by Nguyen et al. (2019) has uncovered a mechanism of Na_V channel inhibition through a new pathway, allowing a hydrophobic molecules to permeate a fenestration between domains III and IV (DIII and DIV) in the human cardiac Nav1.5/β1 channel (Nguyen et al., 2019). It is possible that the hydrophobic PUFA analogue also block Nav1.5/β1 channels through this fenestration between DIII and DIV, causing the voltage-independent decrease in sodium currents.

The molecular mechanism of action of PUFA analogues on Cav1.2/β3/α2δ is still unclear, though we have shown that it does not occur through a shift in the voltage dependence of inactivation. In each case of Cav1.2/β3/α2δ inhibition by PUFA analogues, we observe a dose-dependent decrease in the Ba²⁺ currents that appears as a decrease in G_max. There is evidence that some Ca_V channel antagonists, such as dihydropyridines (DHPs) inhibit Ca_V channels through an allosteric mechanism (Tang et al., 2016). Pepe et al. (1994) found that DHA alters the effectiveness of dihydropyridines, suggesting a shared binding site, or nearby binding sites, for DHPs and PUFAs (Pepe et al., 1994). Tang et al. (2016) found that dihydropyridines bind in a hydrophobic pocket near the pore of the bacterial Ca_vAb channel and cause an allosteric conformational change that leads to disruption of the selectivity filter and thus inhibition of Ca²⁺ currents (Tang et al., 2016). In addition, they observed that in the absence of DHPs a phospholipid occupies the DHP binding site (Tang et al., 2016). This would suggest that it is possible that PUFA analogues inhibit Cav1.2/β3/α2δ by binding to, or near, the DHP binding site and causing an allosteric conformational change that leads to a collapse of the pore and thus explaining the inhibition of Cav1.2/β3/α2δ currents without any changes in the voltage dependence of inactivation.

For simplicity, in this work we co-expressed Kv7.1, Cav1.2, and Nav1.5 with only some of the major auxiliary subunits that have high expression in ventricular cardiac cells to reflect the behavior of ion channel complexes in ventricular cardiomyocytes. For example, Kv7.1 was co-expressed with KCNE1, although other KCNE subunits and other auxiliary subunits, such as Yotiao (Marx et al., 2002), are also found in cardiomyocytes. Auxiliary subunit co-expression is known to modulate the pharmacology of different ion channels. For example, the co-expression of the β1 subunit with Nav1.5 alters PUFA-induced effects by DHA and α-linolenic acid (Xiao et al., 2000). However, we measured inhibition of Nav1.5/β1 by PUFA analogues with a taurine head group, showing that co-expression of the β1 subunit with Nav1.5 does not abolish all type of PUFA-induced inhibition. In addition, the Cav1.2 channel can be co-expressed with different β-subunits, including β3 (which we express in our experiments) and β2 (Buraei and Yang, 2013; Hullin et al., 2003). We found, though, that there are no differences between Cav1.2/β3/α2δ and Cav1.2/β2/α2δ in their response to Lin-taurine and Lin-glycine (Figure 2—figure supplement 1).

Work from several groups has demonstrated a shared electrostatic mechanism of action on voltage-gated K⁺ channels (Liin et al., 2018b) and voltage-gated Na⁺ channels (Ahuja et al., 2015) by biaryl sulfonamides. Liin et al. (2018b) showed that biaryl sulfonamides promote the activation of the Shaker K⁺ channel through an electrostatic effect on the voltage sensing domain. In addition, Ahuja et al. (2015) showed that aryl sulfonamides inhibit Na_V channels through an electrostatic ‘voltage sensor trapping’ mechanism that is specific for the Nav1.7 isoform. The work by Ahuja et al. supports the ability to pharmacologically target different ion channels with a high degree of selectivity (Ahuja et al., 2015). This is in agreement with our findings using PUFA analogues that show that PUFA analogues are variable in their channel selectivity, allowing us to target particular ion channels involved in the ventricular action potential.

It is possible that exogenously applied PUFAs cause changes in membrane properties that indirectly modulate the activity of membrane proteins, including ion channels (G Lee, 2006). For example, the length of the fatty acid acyl chain that incorporates into the membrane can lead to changes in the thickness of the membrane, which could indirectly alter ion channel activity (G Lee, 2006). The PUFA DHA is able to modulate the activity of gramicidin channels via changes in membrane fluidity (Bruno et al., 2007). One basis for the membrane fluidity hypothesis is that some studies found that PUFAs alter the activity of different ion channels at similar concentrations suggesting a similar mechanism (Bruno et al., 2007). However, in this work, we found significant differences in apparent binding affinity of some PUFA analogues for different voltage-gated ion channels expressed in the heart and that some PUFA analogues can modulate some channels selectively while having little to no effect on other cardiac ion channels. These data suggest that it is likely a direct effect on voltage-gated ion channel activity rather than an indirect effect through changes in membrane fluidity, although we cannot rule out that some PUFA analogue effects seen here are due to changes in membrane properties.

Our experiments were mainly conducted using the Xenopus laevis oocyte expression system at room temperature. The membrane composition differs between Xenopus oocytes and mammalian cells, leaving the possibility that Xenopus oocytes lack some signaling molecules and other factors that are present in cardiomyocytes under physiological conditions. For this reason, we conducted experiments in human-induced pluripotent stem cell-derived cardiomyocytes which are more similar to native cardiomyocytes and these experiments were performed at physiological temperatures (37°). Doing this, we found that DHA-glycine is able to shorten the ventricular action potential as expected from experiments in Xenopus oocytes and simulated PUFA-induced effects on cardiomyocytes. We used a slightly higher dose of DHA-glycine (30 μM vs. 7 μM) and got a larger shortening of the APD90 (35% vs 4%) for the experiments on the cardiomyocytes compared to the oocyte experiments and the computer simulations. We tested lower doses of DHA-glycine on the cardiomyocytes but did not get significant effects at low doses. The reason for this is not clear, but it is possible that the cardiomyocytes do not incorporate as much PUFA analogues as oocytes or the affinities of the PUFA analogues for the different ion channels are slightly different in oocytes versus cardiomyocytes. In addition, neither the computer model nor the hiPSC-derived cardiomyocytes are perfect representations of the adult ventricular cardiomyocoytes and they could therefore respond slightly differently to the same stimulus. The main limiting factor with hiPSC-CMs is the level of maturation achieved (Ronaldson-Bouchard et al., 2018; Scuderi and Butcher, 2017). For example, hiPSC-CMs have lower levels of Nav1.5 and Kir2.1 channels (Ronaldson-Bouchard et al., 2018; Verkerk et al., 2017), which could reduce the upstroke velocity of the action potential and generate cardiomyocytes membrane potentials more positive than those usually observed in adult cardiomyocytes, respectively. The ORd computer simulation model has a significantly higher action potential plateau than in adult ventricular cardiomyocytes, the accommodation of the action potential duration in response to sodium changes in the ORd model is not in agreement with experimental data, and sodium channel block has a positive ionotropic effect in the Ord model instead of negative ionotropic effect (Tomek et al., 2019). In addition, the RYR channels dependence on calcium, the L-type Ca²⁺ channels, and the I_Kr channels are not ideally modelled in ORd (Tomek et al., 2019). An updated version of the ORd model that improve on some of these features was published during the review process of this paper (Tomek et al., 2019).

The work presented here demonstrates that PUFA analogues exert diverse modulatory effects on different types of voltage-gated ion channels through non-identical mechanisms. Because PUFA analogues modulate Kv7.1/KCNE1 channels through electrostatic effects, we hypothesized they would have similar effects on Cav1.2/β3/α2δ and Nav1.5/β1 channels. However, our data suggests that PUFA analogues can exert various modulatory effects on the activity of different ion channels, and that the mechanism depends on the ion channel that is being modulated. In addition, we have shown that PUFA analogues exhibit a range of selectivity for different ion channels, which depends both on the PUFA head group and the combination of PUFA head and tail groups. Using simulations of the ventricular action potential, we have shown that selective Kv7.1/KCNE1 channel activators are the most effective at shortening a prolonged ventricular action potential and suppressing early afterdepolarizations induced by hERG block. Last, in hi-PSC derived cardiomyocytes, we found that applying a PUFA analogue that is more selective for the Kv7.1/KCNE1 channel (DHA-glycine) is able to shorten the duration of the ventricular action potential. These data suggest that boosting Kv7.1/KCNE1 currents by using selective Kv7.1/KCNE1 channel activators can aid in restoring a normal action potential duration and prevent early afterdepolarizations.

Molecular Biology cRNA encoding Kv7.1 (UniProt: P51787), KCNE1 (UniProt: P15382.1), Nav1.5 (UniProt: Q14524.1), Nav β1 (UniProt: Q07699.1), Nav β3 (UniProt: Q07699.1), Cav1.2 (GenBank: CAA84346), Cav β3 (Uniprot: P54286), Cav β2 (Uniprot: P54288), and Cav α2δ (Uniprot: P13806) were transcribed using the mMessage mMachine T7 kit (Ambion). 50 ng of cRNA was injected into defolliculated Xenopus laevis oocytes (Ecocyte, Austin, TX): For Kv7.1/KCNE1 channel expression, we injected a 3:1, weight:weight (Kv7.1:KCNE1) cRNA ratio. For Nav1.5 channel expression, we injected a 2:1, weight:weight (Nav1.5:β1) cRNA ratio. For Cav1.2 channel expression, we injected a 2:1:1, weight:weight (Cav1.2:β3:α2δ) cRNA ratio. The exact stoichiometry for channel macromolecular complexes, including α -subunits and auxiliary subunits is not clear for many ion channels. For example, there have been multiple reported stoichiometries for Kv7.1:KCNE1 determined in heterologous expression systems with some groups reporting flexible stoichiometry of 4 Kv7.1: 1–4 KCNE1 and others reporting a fixed stoichiometry of 4 Kv7.1: 2 KCNE1 (Murray et al., 2016; Nakajo et al., 2010). The ratios of cRNA of α- and auxiliary subunits that we injected in Xenopus laevis oocytes are such that all α-subunits are assumed to be in complex with auxiliary subunits. This allows a more homogenous population of ion channels with auxiliary subunits. One caveat to expressing ion channels as macromolecular complexes is that there are many other auxiliary subunits that could associate with the channel α -subunit that are present in cardiomyocytes and have the potential to alter PUFA-induced effects, but that are not being co-expressed in our experiments. In this work, we are co-expressing some of the auxiliary subunits that have been primarily reported to associate with their respective α -subunits in cardiomyocytes. Following cRNA injection, cells were incubated for 72–96 hr in standard ND96 solution (96 mM NaCl, 2 mM KCl, 1 mM MgCl₂, 1.8 mM CaCl₂, 5 mM HEPES; pH = 7.5) containing 1 mM pyruvate at 16°C prior to electrophysiological recordings.

Source data used in this manuscript is openly available and is listed as a source data file for accessibility.

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Author details

1. Briana M Bohannon

   Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, United States

   Contribution

   Formal analysis, Investigation, Writing - original draft, Editing/revision of manuscript

   Contributed equally with

   Alicia de la Cruz

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3720-1477

2. Alicia de la Cruz

   Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, United States

   Contribution

   Formal analysis, Investigation, Writing - original draft, Editing/revision of manuscript

   Contributed equally with

   Briana M Bohannon

   Competing interests

   No competing interests declared

3. Xiaoan Wu

   Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, United States

   Contribution

   Formal analysis, Investigation

   Competing interests

   No competing interests declared

4. Jessica J Jowais

   Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, United States

   Contribution

   Investigation

   Competing interests

   No competing interests declared

5. Marta E Perez

   Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, United States

   Contribution

   Resources, Investigation

   Competing interests

   No competing interests declared

6. Derek M Dykxhoorn

   John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, United States

   Contribution

   Founding acquisition, Resources, Methodology

   Competing interests

   No competing interests declared

7. Sara I Liin

   Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden

   Contribution

   Conceptualization, Resources, Formal analysis, Funding acquisition, Investigation, Editing/revision of manuscript

   Competing interests

   A patent application (62/032,739) has been submitted by the University of Miami with SIL and HPL as inventors. The authors declare no other competing interests

   "This ORCID iD identifies the author of this article:" 0000-0001-8493-0114

8. H Peter Larsson

   Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, United States

   Contribution

   Conceptualization, Formal analysis, Supervision, Funding acquisition, Project administration, Editing/revision of manuscript

   For correspondence

   plarsson@med.miami.edu

   Competing interests

   A patent application (62/032,739) has been submitted by the University of Miami with SIL and HPL as inventors. The authors declare no other competing interests

   "This ORCID iD identifies the author of this article:" 0000-0002-1688-2525

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