| 1. |
- Abdullaeva, Oliya, et al.
(författare)
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Faradaic Pixels for Precise Hydrogen Peroxide Delivery to Control M-Type Voltage-Gated Potassium Channels
- 2022
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Ingår i: Advanced Science. - : Wiley. - 2198-3844. ; 9:3
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Tidskriftsartikel (refereegranskat)abstract
- H2O2 plays a significant role in a range of physiological processes where it performs vital tasks in redox signaling. The sensitivity of many biological pathways to H2O2 opens up a unique direction in the development of bioelectronics devices to control levels of reactive-oxygen species (ROS). Here a microfabricated ROS modulation device that relies on controlled faradaic reactions is presented. A concentric pixel arrangement of a peroxide-evolving cathode surrounded by an anode ring which decomposes the peroxide, resulting in localized peroxide delivery is reported. The conducting polymer (poly(3,4-ethylenedioxythiophene) (PEDOT), is exploited as the cathode. PEDOT selectively catalyzes the oxygen reduction reaction resulting in the production of hydrogen peroxide (H2O2). Using electrochemical and optical assays, combined with modeling, the performance of the devices is benchmarked. The concentric pixels generate tunable gradients of peroxide and oxygen concentrations. The faradaic devices are prototyped by modulating human H2O2-sensitive Kv7.2/7.3 (M-type) channels expressed in a single-cell model (Xenopus laevis oocytes). The Kv7 ion channel family is responsible for regulating neuronal excitability in the heart, brain, and smooth muscles, making it an ideal platform for faradaic ROS stimulation. The results demonstrate the potential of PEDOT to act as an H2O2 delivery system, paving the way to ROS-based organic bioelectronics.
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| 2. |
- Barro-Soria, Rene, et al.
(författare)
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KCNE1 and KCNE3 modulate KCNQ1 channels by affecting different gating transitions
- 2017
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 114:35, s. E7367-E7376
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Tidskriftsartikel (refereegranskat)abstract
- KCNE beta-subunits assemble with and modulate the properties of voltage-gated K+ channels. In the heart, KCNE1 associates with the alpha-subunit KCNQ1 to generate the slowly activating, voltage-dependent potassium current (IKs) in the heart that controls the repolarization phase of cardiac action potentials. By contrast, in epithelial cells from the colon, stomach, and kidney, KCNE3 coassembles with KCNQ1 to form K+ channels that are voltage-independent K+ channels in the physiological voltage range and important for controlling water and salt secretion and absorption. How KCNE1 and KCNE3 subunits modify KCNQ1 channel gating so differently is largely unknown. Here, we use voltage clamp fluorometry to determine how KCNE1 and KCNE3 affect the voltage sensor and the gate of KCNQ1. By separating S4 movement and gate opening by mutations or phosphatidylinositol 4,5-bisphosphate depletion, we show that KCNE1 affects both the S4 movement and the gate, whereas KCNE3 affects the S4 movement and only affects the gate in KCNQ1 if an intact S4-to-gate coupling is present. Further, we show that a triple mutation in the middle of the transmembrane (TM) segment of KCNE3 introduces KCNE1-like effects on the second S4 movement and the gate. In addition, we show that differences in two residues at the external end of the KCNE TM segments underlie differences in the effects of the different KCNEs on the first S4 movement and the voltage sensor-to-gate coupling.
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| 5. |
- 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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| 6. |
- 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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Annan publikation (övrigt vetenskapligt/konstnärligt)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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| 7. |
- Bohannon, Briana M., et al.
(författare)
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omega-6 and omega-9 polyunsaturated fatty acids with double bonds near the carboxyl head have the highest affinity and largest effects on the cardiac I-Ks potassium channel
- 2019
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Ingår i: Acta Physiologica. - : WILEY. - 1748-1708 .- 1748-1716. ; 225:2
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Tidskriftsartikel (refereegranskat)abstract
- Aim The I-Ks channel is important for termination of the cardiac action potential. Hundreds of loss-of-function mutations in the I-Ks channel reduce the K+ current and, thereby, delay the repolarization of the action potential, causing Long QT Syndrome. Long QT predisposes individuals to Torsades de Pointes which can lead to ventricular fibrillation and sudden death. Polyunsaturated fatty acids (PUFAs) are potential therapeutics for Long QT Syndrome, as they affect I-Ks channels. However, it is unclear which properties of PUFAs are essential for their effects on I-Ks channels. Methods To understand how PUFAs influence I-Ks channel activity, we measured effects on I-Ks current by two-electrode voltage clamp while changing different properties of the hydrocarbon tail. Results There was no, or weak, correlation between the tail length or number of double bonds in the tail and the effects on or apparent binding affinity for I-Ks channels. However, we found a strong correlation between the positions of the double bonds relative to the head group and effects on I-Ks channels. Conclusion Polyunsaturated fatty acids with double bonds closer to the head group had higher apparent affinity for I-Ks channels and increased I-Ks current more; shifting the bonds further away from the head group reduced apparent binding affinity for and effects on the I-Ks current. Interestingly, we found that omega-6 and omega-9 PUFAs, with the first double bond closer to the head group, left-shifted the voltage dependence of activation the most. These results allow for informed design of new therapeutics targeting I-Ks channels in Long QT Syndrome.
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| 8. |
- Bohannon, Briana M., et al.
(författare)
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Polyunsaturated fatty acid analogues differentially affect cardiac Na-V, Ca-V, and K-V channels through unique mechanisms
- 2020
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Ingår i: eLIFE. - : ELIFE SCIENCES PUBLICATIONS LTD. - 2050-084X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- The cardiac ventricular action potential depends on several voltage-gated ion channels, including Na-V, Ca-V, and K-V 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 (Na-V, Ca-V, and K-V). 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.
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| 9. |
- Bohannon, Briana M., et al.
(författare)
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Polyunsaturated fatty acids produce a range of activators for heterogeneous I-Ks channel dysfunction
- 2020
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Ingår i: The Journal of General Physiology. - : ROCKEFELLER UNIV PRESS. - 0022-1295 .- 1540-7748. ; 152:2
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Tidskriftsartikel (refereegranskat)abstract
- Repolarization and termination of the ventricular cardiac action potential is highly dependent on the activation of the slow delayed-rectifier potassium I-Ks channel. Disruption of the I-Ks current leads to the most common form of congenital long QT syndrome (LQTS), a disease that predisposes patients to ventricular arrhythmias and sudden cardiac death. We previously demonstrated that polyunsaturated fatty acid (PUFA) analogues increase outward K+ current in wild type and LQTS-causing mutant I-Ks channels. Our group has also demonstrated the necessity of a negatively charged PUFA head group for potent activation of the I-Ks channel through electrostatic interactions with the voltage-sensing and pore domains. Here, we test whether the efficacy of the PUFAs can be tuned by the presence of different functional groups in the PUFA head, thereby altering the electrostatic interactions of the PUFA head group with the voltage sensor or the pore. We show that PUFA analogues with taurine and cysteic head groups produced the most potent activation of I-Ks channels, largely by shifting the voltage dependence of activation. In comparison, the effect on voltage dependence of PUFA analogues with glycine and aspartate head groups was half that of the taurine and cysteic head groups, whereas the effect on maximal conductance was similar. Increasing the number of potentially negatively charged moieties did not enhance the effects of the PUFA on the I-Ks channel. Our results show that one can tune the efficacy of PUFAs on I-Ks channels by altering the pK(a) of the PUFA head group. Different PUFAs with different efficacy on I-Ks channels could be developed into more personalized treatments for LQTS patients with a varying degree of I-Ks channel dysfunction.
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| 10. |
- Castiglione, Alessandro, et al.
(författare)
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Docosahexaenoic acid normalizes QT interval in long QT type 2 transgenic rabbit models in a genotype-specific fashion
- 2022
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Ingår i: Europace. - : OXFORD UNIV PRESS. - 1099-5129 .- 1532-2092. ; 24:3, s. 511-522
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Tidskriftsartikel (refereegranskat)abstract
- Aim Long QT syndrome (LQTS) is a cardiac channelopathy predisposing to ventricular arrhythmias and sudden cardiac death. Since current therapies often fail to prevent arrhythmic events in certain LQTS subtypes, new therapeutic strategies are needed. Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid, which enhances the repolarizing I-Ks current. Methods and results We investigated the effects of DHA in wild type (WT) and transgenic long QT Type 1 (LQT1; loss of I-Ks), LQT2 (loss of I-Kr), LQT5 (reduction of I-Ks), and LQT2-5 (loss of I-Kr and reduction of I-Ks) rabbits. In vivo ECGs were recorded at baseline and after 10 mu M/kg DHA to assess changes in heart-rate corrected QT (QTc) and short-term variability of QT (STVQT). Ex vivo monophasic action potentials were recorded in Langendorff-perfused rabbit hearts, and action potential duration (APD(75)) and triangulation were assessed. Docosahexaenoic acid significantly shortened QTc in vivo only in WT and LQT2 rabbits, in which both alpha- and beta-subunits of I-K(s)-conducting channels are functionally intact. In LQT2, this led to a normalization of QTc and of its short-term variability. Docosahexaenoic acid had no effect on QTc in LQT1, LQT5, and LQT2-5. Similarly, ex vivo, DHA shortened APD(75) in WT and normalized it in LQT2, and additionally decreased AP triangulation in LQT2. Conclusions Docosahexaenoic acid exerts a genotype-specific beneficial shortening/normalizing effect on QTc and APD(75) and reduces pro-arrhythmia markers STVQT and AP triangulation through activation of I-Ks in LQT2 rabbits but has no effects if either alpha- or beta-subunits to I-Ks are functionally impaired. Docosahexaenoic acid could represent a new genotype-specific therapy in LQT2.
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