Travelling through the heart are waves of electrical activity that cause muscle cells to contract and pump blood around the body. The waves are generated by charged ions which flow via tiny channels in and out of the muscle cells. This electrical activity spreads quickly from one cell to the next to make sure all the muscle cells contract at the right time. When these ion channels are compromised, this can lead to heart problems such as long QT syndrome (LQTS).

In patients with LQTS, electrical activity in the heart does not follow the typical rhythm, which can result in an irregular heartbeat and lead to cardiac arrest. The most common cause of LQTS is mutations in the channel KCNQ1, which allows potassium ions to flow out of heart muscle cells. This outflux of potassium restores the electrical charge inside the cell so that it is ready to receive another electrical wave and contract at the right time.

Current treatments for LQTS do not target KCNQ1 channels directly and have side effects. An alternative approach could be to use a group of molecules called polyunsaturated fatty acids (or PUFAs for short) which increase the flow of ions that pass through KCNQ1. However, it is not fully understood how PUFAs achieve this.

Previous research showed that PUFAs activate KCNQ1 via two independent sites: one at the voltage sensor which decides whether the channel is open or closed (Site I), and another at the pore domain ions pass through (Site II). While it is well understood how PUFAs activate the channel at Site I, little is known about the activation mechanism that occurs at Site II.

To investigate, Golluscio et al. modified egg cells from the frog Xenopus laevis to express KCNQ1 channels. Experiments investigating the electrical properties of KCNQ1 revealed that the selective filter in the pore domain – which permits potassium but no other ions to pass through – is usually unstable. However, PUFAs help to stabilize this filter, causing KCNQ1 to stay open more often and allow potassium ions to flow out of muscle cells.

The findings of Golluscio et al. suggest that PUFAs could represent an important therapeutic tool to treat LQTS and potentially other cardiac disorders. However, further studies in heart cells, animals and eventually humans will be required to confirm this conclusion.

The voltage-gated K⁺ channel KCNQ1, also referred to as Kv7.1, is expressed in the heart. Here the channel associates with the accessory KCNE1 subunit, generating the so-called slow delayed-rectifier (IKs) current, an important contributor to the repolarizing phase of the ventricular action potential (AP) (Barhanin et al., 1996; Sanguinetti et al., 1996; Nerbonne and Kass, 2005). Loss-of-function mutations of the KCNQ1/KCNE1 complex are associated with long QT syndrome (LQTS) (Splawski et al., 2000; Tester and Ackerman, 2014). These LQTS mutations cause a reduction of the channel current, leading to a significant prolongation of the ventricular AP waveform that can be seen on the electrocardiogram as a prolonged QT interval (Nerbonne and Kass, 2005; Figure 1A). These channel mutations, or dysfunction, increase the risk of developing cardiac arrhythmias, which can lead to sudden cardiac death (Wu and Sanguinetti, 2016). At present, treatment of LQTS is mainly based on the usage of β-blockers (most used are long-lasting preparations such as nadolol and atenolol) and implantable cardioverter-defibrillators, especially for patients with high risk of sudden death and frequent syncope (Roden, 2008). However, both approaches do not shorten the QT interval duration. Restoring the physiological duration of the QT interval could be achieved by increasing the activity of the KCNQ1/KCNE1 channel complex (Varshneya et al., 2018; Figure 1).

Figure 1

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Figure 1—source data 1

Tail current data used to generate Figure 1C.

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Like other Kv channels, KCNQ1 has a typical tetrameric structure of four α-subunits. Each α-subunit is composed of six transmembrane segments, with S1-S4 forming the voltage sensor domain (VSD) and S5-S6 forming the pore domain (PD) (Figure 1D). However, the KCNQ1/KCNE1 channel complex has a very small single-channel conductance and a very low open probability compared to other Kv channels (Werry et al., 2013). The mechanisms behind the small conductance and low open probability are not understood.

Polyunsaturated fatty acids (PUFA), in particular omega 3, are known to exert a protective effect on sudden cardiac death and are recommended in the diet at least twice a week (Fernandez et al., 2021). PUFAs have been shown to increase IKs currents by a dual mechanism of action, characteristically described as a ‘Lipoelectric mechanism’ (Elinder and Liin, 2017). According to this mechanism, PUFAs can increase IKs currents by shifting the voltage dependence of activation (ΔV0.5) toward negative voltages and increase the maximum conductance of the channel (ΔGmax) (Bohannon et al., 2019; Bohannon et al., 2020; Yazdi et al., 2021; Larsson et al., 2020; Wu and Larsson, 2020; Figure 1B and C).

The two PUFA effects (ΔV0.5 and ΔGmax) on KCNQ1 are independent of each other and originate from the binding of PUFA to two different sites, conventionally indicated as Site I and Site II (Yazdi et al., 2021; Liin et al., 2018). Site I is found in the VSD, where the PUFA head group interacts with the positive charges in the S4 segment and causes the channel to open at more negative potentials (Liin et al., 2015). Site II is found in the pore domain, where electrostatic interactions between the PUFA head group and the positively charged residue, K326, facilitate an increase in the maximal conductance of the channel (Liin et al., 2018; Figure 1E and F).

Although previous studies have shown the importance of K326 for PUFA in increasing Gmax through binding at Site II (Liin et al., 2018), the mechanism by which PUFAs increase Gmax is still not understood. In this study, we use a combination of two-electrode voltage-clamp, single-channel recordings, site-directed mutagenesis, and recent cryoEM structures to gain insight into the molecular mechanism underlying the Gmax effect following PUFA binding at Site II. We propose a novel mechanism where the selectivity filter of KCNQ1 is normally unstable and the binding of PUFA to Site II stabilizes a network of interactions at the selectivity filter, which, in turn, leads to a more open and stable conformation of the KCNQ1 pore and thus an increase in channel open probability.

We have previously proposed models in which the effect of PUFAs on IKs channels involve the binding of PUFAs to two independent sites: one at the voltage sensor (Site I) and one at the pore domain (Site II). The result is a potent activation of IKs channels, with an increase in the maximum conductance by binding to Site II and a shift of the voltage dependence of activation of the channel by binding to Site I. The mechanism of the voltage shift effects at Site I, where the PUFA head group electrostatically interacts with positively charged S4 residues and thereby facilitates channel activation, has been investigated in previous studies (Yazdi et al., 2021; Bohannon et al., 2023; Liin et al., 2018; Jowais et al., 2023). However, less is known about the molecular mechanism by which PUFA increases the maximum conductance (Gmax) of the channel following binding to Site II. A positively charged lysine at position 326 was suggested to be critical for PUFA-channel interaction, as mutations of K326 completely abolished the Gmax effect (Liin et al., 2018). We have here shown that the interaction at Site II also involves another residue, the aspartic acid 301, as mutagenesis analysis revealed that the effect of Lin-Glycine on Gmax was abolished when the residue was substituted with a glutamic acid.

Our single-channel recordings revealed that Lin-Glycine decreases the latency to first opening and increases the Po. The decrease in the latency to first opening is most likely due to the binding of Lin-Glycine to Site I at the VSD and related to the shift in voltage dependence caused by Lin-Glycine (Figure 2—figure supplement 1). In addition, our single-channel recordings revealed that Lin-Glycine did not change the single-channel conductance, but instead increased Gmax by increasing the Po of the channel. This increase in Po was mainly due to an increase in non-empty sweeps when Lin-Glycine was applied in comparison to control solutions.

We tested the hypothesis that the effect of Lin-Glycine involved conformational changes in the selectivity filter following PUFA binding to two residues K326 and D301 at the pore domain. Those residues delimit a small crevice that seems to change in size in different structures with S4 activated or resting (Figure 3D–F) and seem to affect PUFA’s ability to increase Gmax. We made several mutations in residues known to stabilize the selectivity filter of potassium channels (Y315F, D317E, T309S, and P320L; Figure 5A). The Lin-Glycine effect on the Gmax was much reduced in these mutants, suggesting that these residues are necessary for the Gmax effect. To gain further insight into the molecular interactions that could underline the Gmax effect by PUFA binding to Site II, we used the latest KCNQ1 structure with the S4 segment in the resting state (Mandala and MacKinnon, 2023). The selectivity filter in this structure showed a very different conformation of the pore region and selectivity filter of KCNQ1 compared to the structures with activated VSDs. Clearly, there will be other differences in the pore domain between structures with activated and resting VSDs, for example, the state of the activation gate. Many of the interactions that have been shown to be important for the stability of the selectivity filter are missing in the KCNQ1 structure with a resting VSD. These changes in the selectivity filter can best be seen in our interpolation video between the states with the S4 segments moving from the resting state to the activated state (Video 1). This gave us the idea that the effect of PUFAs in increasing the maximum conductance of the KCNQ1 channel is linked to their ability to stabilize the pore of the channel in a conductive state. It was previously shown that several interactions at the pore region of K⁺ channels are important for ensuring channel conductivity. For example, a feature conserved among K⁺ channels is the aromatic ring cuff that stabilizes the conducting state and plays a role in C-type inactivation (Doyle et al., 1998; Larsson and Elinder, 2000; Pless et al., 2013; Kurata and Fedida, 2006). This structure is made up of two tryptophan residues (W) and a proline residue (P) that sits in between the two tryptophan residues (Video 2). In Shaker and KcsA K⁺ channels, the two tryptophans are involved in C-type inactivation and modification of those interactions manipulate the extent of inactivation (Cordero-Morales et al., 2011; Yang et al., 1997). In Shaker, breaking the hydrogen bonds between the two tryptophans of the aromatic ring cuff and the aspartic acid and tyrosine at the selectivity filter causes an acceleration of the rate of C-type inactivation (Pless et al., 2013). In KCNQ1, the two tryptophans of the aromatic ring cuff correspond to W304 and W305. Another conserved residue in K⁺ channels important for the stability of the selectivity filter is P320 (equivalent to P450 in Shaker) that makes up part of the aromatic ring cuff. In the transition between the non-conductive and conductive state of KCNQ1, the proline pulls away from its position close to W304 and W305 and flips outward (Video 2). We hypothesize that those hydrogen bonds between W304-D317 and W305-Y315 and the proline interactions are likely absent in the non-conductive conformation of KCNQ1, thereby generating the high number of empty sweeps in control conditions. Occasionally the channel will reform these bonds and interactions and transition into the conductive conformation, thereby generating the non-empty sweeps. We hypothesize that the binding of Lin-Glycine to K326 and D301 at Site II biases the transition toward the conductive conformation, thereby increasing the number of non-empty sweeps and increasing Gmax. We here show that mutations of residues involved in these hydrogen bonds in the selectivity filter greatly reduce or abolish the Gmax effect of Lin-Glycine, as if Lin-Glycine increases the Gmax by stabilizing a conductive state of the selectivity filter through these hydrogen bonds.

We noticed that the arrangement of the aromatic ring cuff is slightly different between Shaker K⁺ channels and KCNQ1 channel. For instance, in Shaker, the proline residue sits in between the two tryptophan residues and stabilizes the aromatic ring cuff (Figure 4—figure supplement 3A). In contrast, in KCNQ1 the proline is positioned a little further outward and away from the two tryptophan residues, thus generating a looser arrangement of the aromatic ring cuff (Figure 4—figure supplement 3B). This difference might contribute to rendering the pore of KCNQ1 more unstable, resulting in a large number of empty sweeps and the characteristic flickering nature of channel openings (Eldstrom et al., 2021). In Shaker channels, the aromatic cuff seems more stable since it displays few empty sweeps and less flicker during bursts. This difference in the stability of the aromatic cuff between Shaker and KCNQ1 might explain why the effect of PUFA on Gmax is large for KCNQ1 but not seen in Shaker (Börjesson et al., 2008; Börjesson and Elinder, 2011) even if the residues involved in the Gmax effect are conserved between these two channels.

Our single-channel data show that the KCNQ1/KCNE1 switches slowly (>10 s) between conductive and non-conductive states, giving rise to many empty sweeps and few active sweeps. However, once the channel becomes conductive during a depolarization, the channel stays conductive for the remainder of the sweep (see, e.g., Figure 2—figure supplement 2 for 20 s sweeps), as if VSD activation stabilizes the conductive state. Therefore, we propose a model in which the selectivity filter is stabilized more in the non-conductive state when VSD is resting but stabilized more in the conductive state when VSD is activated. This model is consistent with the cryoEM structures of KCNQ1 with VSD resting displaying a non-conductive selectivity filter and with VSD activated displaying a conductive selectivity filter (Mandala and MacKinnon, 2023). The KCNQ1 structure with VSD resting was obtained in a low K⁺ solution, which in other Kv channels would promote C-type inactivation of the selectivity filter. However, we think it is the resting state of the VSD, and not the low K⁺, that caused the non-conductive selectivity filter in the KCNQ1 structure because a KCNQ1 structure with VSD activated in the low K⁺ solution had a selectivity filter that was nearly identical to the KCNQ1 structure in high K⁺ with VSD activated (except for fewer K⁺ ions in the filter in low K⁺ solutions) (see Suppl. Figs. S5C and S5D in Mandala and MacKinnon, 2023). Note also the currents from KCNQ1/KCNE1 channels display little external K⁺ dependence (a small inhibition in addition to what is expected from changes in driving force) and that KCNQ1 channels are more strongly inhibited by high extracellular K⁺ concentrations (Abrahamyan et al., 2023; Larsen et al., 2011) in contrast to other Kv channels, such as Shaker K⁺ channels, which are inactivated more in low K⁺ (Larsson and Elinder, 2000; Kurata and Fedida, 2006). Our studies suggest that the mechanism of PUFAs to increase KCNQ1/KCNE1 maximum conductance relies on the ability of PUFAs to favor the conductive conformation of the selectivity filter: PUFAs promote interactions between residues in the selectivity filter that stabilize the channel pore. Furthermore, we identify a crevice between K326 and D301 that is present in structures of KCNQ1 with activated VSD but not in structures where the VSD is in the resting state. We propose that PUFA binding in this crevice stabilizes the network of interactions that form the conductive form of the selectivity filter. The result is a more stable and conductive pore, which explains the increase in Gmax by PUFAs.

All data generated or analysed during this study are included in the manuscript and supporting files; source data files have been provided for Figures 1, 3, 5 and 6, Figure 3—figure supplement 1, Figure 5—figure supplements 1 and 2. Figure 1—source data 1, Figure 3—source data 1, Figure 5—source data 1, Figure 6—source data 1, Figure 3—figure supplement 1—source data 1, Figure 5—figure supplement 1—source data 1, Figure 5—figure supplement 2—source data 1 contain the numerical data used to generate these figures.

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Author details

1. Alessia Golluscio

   1. Department of Physiology and Biophysics, University of Miami, Miami, United States
   2. Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4556-9869

2. Jodene Eldstrom

   Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada

   Contribution

   Data curation, Formal analysis, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

3. Jessica J Jowais

   Department of Physiology and Biophysics, University of Miami, Miami, United States

   Contribution

   Data curation, Formal analysis, Investigation

   Competing interests

   No competing interests declared

4. Marta Elena Perez

   Department of Physiology and Biophysics, University of Miami, Miami, United States

   Contribution

   Investigation

   Competing interests

   No competing interests declared

5. Kevin Peter Cunningham

   1. Department of Physiology and Biophysics, University of Miami, Miami, United States
   2. School of Life Sciences, University of Westminster, London, United Kingdom

   Contribution

   Data curation, Formal analysis, Investigation

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-6772-0107

6. Alicia De La Cruz

   1. Department of Physiology and Biophysics, University of Miami, Miami, United States
   2. Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden

   Contribution

   Data curation, Formal analysis, Investigation

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-0349-4881

7. Xiaoan Wu

   Department of Physiology and Biophysics, University of Miami, Miami, United States

   Contribution

   Data curation, Formal analysis, Investigation

   Competing interests

   No competing interests declared

8. Valentina Corradi

   Department of Biological Sciences and Centre for Molecular Simulation, University of Calgary, Calgary, Canada

   Contribution

   Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

9. D Peter Tieleman

   Department of Biological Sciences and Centre for Molecular Simulation, University of Calgary, Calgary, Canada

   Contribution

   Resources, Formal analysis, Supervision, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5507-0688

10. David Fedida

    Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada

    Contribution

    Formal analysis, Supervision, Writing – original draft, Writing – review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-6797-5185

11. H Peter Larsson

    1. Department of Physiology and Biophysics, University of Miami, Miami, United States
    2. Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden

    Contribution

    Formal analysis, Supervision, Writing – original draft, Project administration, Writing – review and editing

    For correspondence

    peter.larsson@liu.se

    Competing interests

    No competing interests declared

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

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