| 1. |
- Bohannon, Briana M., et al.
(författare)
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Mechanistic insights into robust cardiac I-Ks potassium channel activation by aromatic polyunsaturated fatty acid analogues
- 2023
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Ingår i: eLIFE. - : eLIFE SCIENCES PUBL LTD. - 2050-084X. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Voltage-gated potassium (K-V) channels are important regulators of cellular excitability and control action potential repolarization in the heart and brain. K-V channel mutations lead to disordered cellular excitability. Loss-of-function mutations, for example, result in membrane hyperexcitability, a characteristic of epilepsy and cardiac arrhythmias. Interventions intended to restore K-V channel function have strong therapeutic potential in such disorders. Polyunsaturated fatty acids (PUFAs) and PUFA analogues comprise a class of K-V channel activators with potential applications in the treatment of arrhythmogenic disorders such as long QT syndrome (LQTS). LQTS is caused by a loss-of-function of the cardiac I-Ks channel - a tetrameric potassium channel complex formed by K(V)7.1 and associated KCNE1 protein subunits. We have discovered a set of aromatic PUFA analogues that produce robust activation of the cardiac I-Ks channel, and a unique feature of these PUFA analogues is an aromatic, tyrosine head group. We determine the mechanisms through which tyrosine PUFA analogues exert strong activating effects on the I-Ks channel by generating modified aromatic head groups designed to probe cation-pi interactions, hydrogen bonding, and ionic interactions. We found that tyrosine PUFA analogues do not activate the I-Ks channel through cation-pi interactions, but instead do so through a combination of hydrogen bonding and ionic interactions.
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| 2. |
- Yazdi, Samira, et al.
(författare)
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Identification of PUFA interaction sites on the cardiac potassium channel KCNQ1
- 2021
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Ingår i: The Journal of General Physiology. - : ROCKEFELLER UNIV PRESS. - 0022-1295 .- 1540-7748. ; 153:6
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Tidskriftsartikel (refereegranskat)abstract
- Polyunsaturated fatty acids (PUFAs) affect many different ion channels, such as voltage-gated K+, Na+, and Ca2+ channels, as well as ryanodine receptors (Xiao et al., 2001; Hamilton et al., 2003; Oliver et al., 2004; Xiao et al., 2005; Ottosson et al., 2014; Farag et al., 2016; Tian et al., 2016; Liin et al., 2018; Bohannon et al., 2020). However, the molecular mechanisms behind the effects of PUFAs are not completely understood. The identity of PUFAs specific binding pockets remains uncharacterized for many ion channels; therefore, the molecular mechanisms of Polyunsaturated fatty acids (PUFAs), but not saturated fatty acids, modulate ion channels such as the cardiac KCNQ1 channel, although the mechanism is not completely understood. Using both simulations and experiments, we find that PUFAs interact directly with the KCNQ1 channel via two different binding sites: one at the voltage sensor and one at the pore. These two amphiphilic binding pockets stabilize the negatively charged PUFA head group by electrostatic interactions with R218, R221, and K316, while the hydrophobic PUFA tail is selectively stabilized by cassettes of hydrophobic residues. The rigid saturated tail of stearic acid prevents close contacts with KCNQ1. By contrast, the mobile tail of PUFA linoleic acid can be accommodated in the crevice of the hydrophobic cassette, a defining feature of PUFA selectivity in KCNQ1. In addition, we identify Y268 as a critical PUFA anchor point underlying fatty acid selectivity. Combined, this study provides molecular models of direct interactions between PUFAs and KCNQ1 and identifies selectivity mechanisms. Long term, this understanding may open new avenues for drug development based on PUFA mechanisms.
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| 3. |
- Hiniesto Iñigo, Irene, et al.
(författare)
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Endocannabinoids enhance hKV7.1/KCNE1 channel function and shorten the cardiac action potential and QT interval
- 2023
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Ingår i: EBioMedicine. - : ELSEVIER. - 2352-3964. ; 89
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Tidskriftsartikel (refereegranskat)abstract
- Background Genotype-positive patients who suffer from the cardiac channelopathy Long QT Syndrome (LQTS) may display a spectrum of clinical phenotypes, with often unknown causes. Therefore, there is a need to identify factors influencing disease severity to move towards an individualized clinical management of LQTS. One possible factor influencing the disease phenotype is the endocannabinoid system, which has emerged as a modulator of cardio-vascular function. In this study, we aim to elucidate whether endocannabinoids target the cardiac voltage-gated potassium channel KV7.1/KCNE1, which is the most frequently mutated ion channel in LQTS.Methods We used two-electrode voltage clamp, molecular dynamics simulations and the E4031 drug-induced LQT2 model of ex-vivo guinea pig hearts.Findings We found a set of endocannabinoids that facilitate channel activation, seen as a shifted voltage-dependence of channel opening and increased overall current amplitude and conductance. We propose that negatively charged endocannabinoids interact with known lipid binding sites at positively charged amino acids on the channel, providing structural insights into why only specific endocannabinoids modulate KV7.1/KCNE1. Using the endocannabinoid ARA-S as a prototype, we show that the effect is not dependent on the KCNE1 subunit or the phosphorylation state of the channel. In guinea pig hearts, ARA-S was found to reverse the E4031-prolonged action potential duration and QT interval. Interpretation We consider the endocannabinoids as an interesting class of hKV7.1/KCNE1 channel modulators with putative protective effects in LQTS contexts.Copyright (c) 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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| 4. |
- Jämbeck, Joakim P. M., 1986-
(författare)
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Computer Simulations of Heterogenous Biomembranes
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Molecular modeling has come a long way during the past decades and in the current thesis modeling of biological membranes is the focus. The main method of choice has been classical Molecular Dynamics simulations and for this technique a model Hamiltonian, or force field (FF), has been developed for lipids to be used for biological membranes. Further, ways of more accurately simulate the interactions between solutes and membranes have been investigated.A FF coined Slipids was developed and validated against a range of experimental data (Papers I-III). Several structural properties such as area per lipid, scattering form factors and NMR order parameters obtained from the simulations are in good agreement with available experimental data. Further, the compatibility of Slipids with amino acid FFs was proven. This, together with the wide range of lipids that can be studied, makes Slipids an ideal candidate for large-scale studies of biologically relevant systems.A solute's electron distribution is changed as it is transferred from water to a bilayer, a phenomena that cannot be fully captured with fixed-charge FFs. In Paper IV we propose a scheme of implicitly including these effects with fixed-charge FFs in order to more realistically model water-membrane partitioning. The results are in good agreement with experiments in terms of free energies and further the differences between using this scheme and the more traditional approach were highlighted.The free energy landscape (FEL) of solutes embedded in a model membrane is explored in Paper V. This was done using biased sampling methods with a reaction coordinate that included intramolecular degrees of freedom (DoF). These DoFs were identified in different bulk liquids and then used in studies with bilayers. The FELs describe the conformational changes necessary for the system to follow the lowest free energy path. Besides this, the pitfalls of using a one-dimensional reaction coordinate are highlighted.
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