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  1. Article ; Online: Modeling the Hidden Pathways of IKs Channel Activation.

    Fedida, David

    Biophysical journal

    2018  Volume 115, Issue 1, Page(s) 1–2

    MeSH term(s) Ion Channels ; KCNQ1 Potassium Channel ; Potassium Channels, Voltage-Gated
    Chemical Substances Ion Channels ; KCNQ1 Potassium Channel ; Potassium Channels, Voltage-Gated
    Language English
    Publishing date 2018-09-19
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 218078-9
    ISSN 1542-0086 ; 0006-3495
    ISSN (online) 1542-0086
    ISSN 0006-3495
    DOI 10.1016/j.bpj.2018.05.020
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  2. Article ; Online: Evaluating sequential and allosteric activation models in IKs channels with mutated voltage sensors.

    Fedida, David / Sastre, Daniel / Dou, Ying / Westhoff, Maartje / Eldstrom, Jodene

    The Journal of general physiology

    2024  Volume 156, Issue 3

    Abstract: The ion-conducting IKs channel complex, important in cardiac repolarization and arrhythmias, comprises tetramers of KCNQ1 α-subunits along with 1-4 KCNE1 accessory subunits and calmodulin regulatory molecules. The E160R mutation in individual KCNQ1 ... ...

    Abstract The ion-conducting IKs channel complex, important in cardiac repolarization and arrhythmias, comprises tetramers of KCNQ1 α-subunits along with 1-4 KCNE1 accessory subunits and calmodulin regulatory molecules. The E160R mutation in individual KCNQ1 subunits was used to prevent activation of voltage sensors and allow direct determination of transition rate data from complexes opening with a fixed number of 1, 2, or 4 activatable voltage sensors. Markov models were used to test the suitability of sequential versus allosteric models of IKs activation by comparing simulations with experimental steady-state and transient activation kinetics, voltage-sensor fluorescence from channels with two or four activatable domains, and limiting slope currents at negative potentials. Sequential Hodgkin-Huxley-type models approximately describe IKs currents but cannot explain an activation delay in channels with only one activatable subunit or the hyperpolarizing shift in the conductance-voltage relationship with more activatable voltage sensors. Incorporating two voltage sensor activation steps in sequential models and a concerted step in opening via rates derived from fluorescence measurements improves models but does not resolve fundamental differences with experimental data. Limiting slope current data that show the opening of channels at negative potentials and very low open probability are better simulated using allosteric models of activation with one transition per voltage sensor, which implies that movement of all four sensors is not required for IKs conductance. Tiered allosteric models with two activating transitions per voltage sensor can fully account for IKs current and fluorescence activation kinetics in constructs with different numbers of activatable voltage sensors.
    MeSH term(s) Allosteric Regulation ; KCNQ1 Potassium Channel ; Calmodulin ; Heart ; Kinetics
    Chemical Substances KCNQ1 Potassium Channel ; Calmodulin
    Language English
    Publishing date 2024-01-31
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3118-5
    ISSN 1540-7748 ; 0022-1295
    ISSN (online) 1540-7748
    ISSN 0022-1295
    DOI 10.1085/jgp.202313465
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  3. Article ; Online: In Silico Evaluation of Hexamethylene Amiloride Derivatives as Potential Luminal Inhibitors of SARS-CoV-2 E Protein.

    Jalily, Pouria H / Jalily Hasani, Horia / Fedida, David

    International journal of molecular sciences

    2022  Volume 23, Issue 18

    Abstract: The coronavirus E proteins are small membrane proteins found in the virus envelope of alpha and beta coronaviruses that have a high degree of overlap in their biochemical and functional properties despite minor sequence variations. The SARS-CoV-2 E is a ... ...

    Abstract The coronavirus E proteins are small membrane proteins found in the virus envelope of alpha and beta coronaviruses that have a high degree of overlap in their biochemical and functional properties despite minor sequence variations. The SARS-CoV-2 E is a 75-amino acid transmembrane protein capable of acting as an ion channel when assembled in a pentameric fashion. Various studies have found that hexamethylene amiloride (HMA) can inhibit the ion channel activity of the E protein in bilayers and also inhibit viral replication in cultured cells. Here, we use the available structural data in conjunction with homology modelling to build a comprehensive model of the E protein to assess potential binding sites and molecular interactions of HMA derivatives. Furthermore, we employed an iterative cycle of molecular modelling, extensive docking simulations, molecular dynamics and leveraging steered molecular dynamics to better understand the pore characteristics and quantify the affinity of the bound ligands. Results from this work highlight the potential of acylguanidines as blockers of the E protein and guide the development of subsequent small molecule inhibitors.
    MeSH term(s) Amiloride/analogs & derivatives ; Amiloride/pharmacology ; Amino Acids ; COVID-19/drug therapy ; Humans ; Ion Channels/metabolism ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; SARS-CoV-2
    Chemical Substances Amino Acids ; Ion Channels ; 5-(N,N-hexamethylene)amiloride (1428-95-1) ; Amiloride (7DZO8EB0Z3)
    Language English
    Publishing date 2022-09-13
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms231810647
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  4. Article ; Online: The Emergence of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPSC-CMs) as a Platform to Model Arrhythmogenic Diseases.

    Pourrier, Marc / Fedida, David

    International journal of molecular sciences

    2020  Volume 21, Issue 2

    Abstract: There is a need for improved in vitro models of inherited cardiac diseases to better understand basic cellular and molecular mechanisms and advance drug development. Most of these diseases are associated with arrhythmias, as a result of mutations in ion ... ...

    Abstract There is a need for improved in vitro models of inherited cardiac diseases to better understand basic cellular and molecular mechanisms and advance drug development. Most of these diseases are associated with arrhythmias, as a result of mutations in ion channel or ion channel-modulatory proteins. Thus far, the electrophysiological phenotype of these mutations has been typically studied using transgenic animal models and heterologous expression systems. Although they have played a major role in advancing the understanding of the pathophysiology of arrhythmogenesis, more physiological and predictive preclinical models are necessary to optimize the treatment strategy for individual patients. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have generated much interest as an alternative tool to model arrhythmogenic diseases. They provide a unique opportunity to recapitulate the native-like environment required for mutated proteins to reproduce the human cellular disease phenotype. However, it is also important to recognize the limitations of this technology, specifically their fetal electrophysiological phenotype, which differentiates them from adult human myocytes. In this review, we provide an overview of the major inherited arrhythmogenic cardiac diseases modeled using hiPSC-CMs and for which the cellular disease phenotype has been somewhat characterized.
    MeSH term(s) Action Potentials ; Arrhythmias, Cardiac/congenital ; Arrhythmias, Cardiac/genetics ; Arrhythmias, Cardiac/physiopathology ; Cell Differentiation ; Cells, Cultured ; Humans ; Induced Pluripotent Stem Cells/cytology ; Induced Pluripotent Stem Cells/metabolism ; Ion Channels/genetics ; Ion Channels/metabolism ; Models, Biological ; Myocytes, Cardiac/cytology ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology
    Chemical Substances Ion Channels
    Language English
    Publishing date 2020-01-19
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms21020657
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  5. Article: Gating and Regulation of KCNQ1 and KCNQ1 + KCNE1 Channel Complexes.

    Wang, Yundi / Eldstrom, Jodene / Fedida, David

    Frontiers in physiology

    2020  Volume 11, Page(s) 504

    Abstract: The IKs channel complex is formed by the co-assembly of Kv7.1 (KCNQ1), a voltage-gated potassium channel, with its β-subunit, KCNE1 and the association of numerous accessory regulatory molecules such as PIP2, calmodulin, and yotiao. As a result, the IKs ... ...

    Abstract The IKs channel complex is formed by the co-assembly of Kv7.1 (KCNQ1), a voltage-gated potassium channel, with its β-subunit, KCNE1 and the association of numerous accessory regulatory molecules such as PIP2, calmodulin, and yotiao. As a result, the IKs potassium current shows kinetic and regulatory flexibility, which not only allows IKs to fulfill physiological roles as disparate as cardiac repolarization and the maintenance of endolymph K
    Language English
    Publishing date 2020-06-04
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2564217-0
    ISSN 1664-042X
    ISSN 1664-042X
    DOI 10.3389/fphys.2020.00504
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  6. Article ; Online: Hormonal Signaling Actions on Kv7.1 (KCNQ1) Channels.

    Thompson, Emely / Eldstrom, Jodene / Fedida, David

    Annual review of pharmacology and toxicology

    2020  Volume 61, Page(s) 381–400

    Abstract: Kv7 channels (Kv7.1-7.5) are voltage-gated ... ...

    Abstract Kv7 channels (Kv7.1-7.5) are voltage-gated K
    MeSH term(s) Action Potentials ; Humans ; KCNQ1 Potassium Channel/metabolism ; Potassium Channels, Voltage-Gated/metabolism ; Protein Binding ; Signal Transduction
    Chemical Substances KCNQ1 Potassium Channel ; KCNQ1 protein, human ; Potassium Channels, Voltage-Gated
    Keywords covid19
    Language English
    Publishing date 2020-07-15
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 196587-6
    ISSN 1545-4304 ; 0362-1642
    ISSN (online) 1545-4304
    ISSN 0362-1642
    DOI 10.1146/annurev-pharmtox-010919-023645
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  7. Article ; Online: A novel ion conducting route besides the central pore in an inherited mutant of G-protein-gated inwardly rectifying K

    Chen, I-Shan / Eldstrom, Jodene / Fedida, David / Kubo, Yoshihiro

    The Journal of physiology

    2021  Volume 600, Issue 3, Page(s) 603–622

    Abstract: G-protein-gated inwardly rectifying ... ...

    Abstract G-protein-gated inwardly rectifying K
    MeSH term(s) Animals ; G Protein-Coupled Inwardly-Rectifying Potassium Channels/genetics ; GTP-Binding Proteins ; Mice ; Mutation ; Oocytes/physiology
    Chemical Substances G Protein-Coupled Inwardly-Rectifying Potassium Channels ; Kcnj6 protein, mouse ; GTP-Binding Proteins (EC 3.6.1.-)
    Language English
    Publishing date 2021-12-29
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3115-x
    ISSN 1469-7793 ; 0022-3751
    ISSN (online) 1469-7793
    ISSN 0022-3751
    DOI 10.1113/JP282430
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  8. Article ; Online: A generic binding pocket for small molecule

    Chan, Magnus / Sahakyan, Harutyun / Eldstrom, Jodene / Sastre, Daniel / Wang, Yundi / Dou, Ying / Pourrier, Marc / Vardanyan, Vitya / Fedida, David

    eLife

    2023  Volume 12

    Abstract: ... The ... ...

    Abstract The cardiac
    MeSH term(s) Animals ; KCNQ1 Potassium Channel/genetics ; Calmodulin/genetics ; Heart ; Heart Rate ; Immunologic Factors ; Mammals
    Chemical Substances KCNQ1 Potassium Channel ; Calmodulin ; Immunologic Factors
    Language English
    Publishing date 2023-09-14
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.87038
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  9. Article ; Online: The

    Wang, Yundi / Eldstrom, Jodene / Fedida, David

    Molecular pharmacology

    2019  Volume 97, Issue 2, Page(s) 132–144

    Abstract: The pairing of KCNQ1 and KCNE1 subunits together mediates the cardiac slow delayed rectifier current ( ...

    Abstract The pairing of KCNQ1 and KCNE1 subunits together mediates the cardiac slow delayed rectifier current (
    MeSH term(s) Animals ; Anti-Arrhythmia Agents/pharmacology ; Anti-Arrhythmia Agents/therapeutic use ; Arrhythmias, Cardiac/drug therapy ; Arrhythmias, Cardiac/physiopathology ; Dose-Response Relationship, Drug ; Fibroblasts ; HEK293 Cells ; Heart Rate/physiology ; Humans ; Ion Channel Gating/drug effects ; KCNQ1 Potassium Channel/chemistry ; KCNQ1 Potassium Channel/genetics ; KCNQ1 Potassium Channel/metabolism ; Mefenamic Acid/pharmacology ; Membrane Potentials/drug effects ; Mice ; Mutagenesis, Site-Directed ; Mutation ; Myocardium/metabolism ; Patch-Clamp Techniques ; Potassium/metabolism ; Potassium Channels, Voltage-Gated/agonists ; Potassium Channels, Voltage-Gated/chemistry ; Potassium Channels, Voltage-Gated/genetics ; Potassium Channels, Voltage-Gated/metabolism ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Signal Transduction/drug effects
    Chemical Substances Anti-Arrhythmia Agents ; KCNE1 protein, human ; KCNQ1 Potassium Channel ; KCNQ1 protein, human ; Potassium Channels, Voltage-Gated ; Recombinant Proteins ; Mefenamic Acid (367589PJ2C) ; Potassium (RWP5GA015D)
    Language English
    Publishing date 2019-11-13
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 124034-1
    ISSN 1521-0111 ; 0026-895X
    ISSN (online) 1521-0111
    ISSN 0026-895X
    DOI 10.1124/mol.119.117952
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  10. Article ; Online: hERG long QT syndrome type 2 mutants need more than a chaperone to dance.

    Fedida, David / Macdonald, Logan

    The Journal of physiology

    2016  Volume 594, Issue 15, Page(s) 4095–4096

    Language English
    Publishing date 2016-08-01
    Publishing country England
    Document type Journal Article
    ZDB-ID 3115-x
    ISSN 1469-7793 ; 0022-3751
    ISSN (online) 1469-7793
    ISSN 0022-3751
    DOI 10.1113/JP272417
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