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  1. Article ; Online: KCNQ1 rescues TMC1 plasma membrane expression but not mechanosensitive channel activity.

    Harkcom, William T / Papanikolaou, Maria / Kanda, Vikram / Crump, Shawn M / Abbott, Geoffrey W

    Journal of cellular physiology

    2019  Volume 234, Issue 8, Page(s) 13361–13369

    Abstract: Transmembrane channel-like protein isoform 1 (TMC1) is essential for the generation of mechano-electrical transducer currents in hair cells of the inner ear. TMC1 disruption causes hair cell degeneration and deafness in mice and humans. Although thought ... ...

    Abstract Transmembrane channel-like protein isoform 1 (TMC1) is essential for the generation of mechano-electrical transducer currents in hair cells of the inner ear. TMC1 disruption causes hair cell degeneration and deafness in mice and humans. Although thought to be expressed at the cell surface in vivo, TMC1 remains in the endoplasmic reticulum when heterologously expressed in standard cell lines, precluding determination of its roles in mechanosensing and pore formation. Here, we report that the KCNQ1 Kv channel forms complexes with TMC1 and rescues its surface expression when coexpressed in Chinese Hamster Ovary cells. TMC1 rescue is specific for KCNQ1 within the KCNQ family, is prevented by a KCNQ1 trafficking-deficient mutation, and is influenced by KCNE β subunits and inhibition of KCNQ1 endocytosis. TMC1 lowers KCNQ1 and KCNQ1-KCNE1 K
    MeSH term(s) Amino Acid Motifs ; Animals ; CHO Cells ; COS Cells ; Cell Membrane/metabolism ; Chlorocebus aethiops ; Cricetulus ; Female ; Hair Cells, Auditory, Inner/metabolism ; Humans ; KCNQ1 Potassium Channel/chemistry ; KCNQ1 Potassium Channel/genetics ; KCNQ1 Potassium Channel/metabolism ; Mechanotransduction, Cellular/genetics ; Mechanotransduction, Cellular/physiology ; Membrane Potentials ; Membrane Proteins/chemistry ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice ; Mutagenesis, Site-Directed ; Oocytes/metabolism ; Patch-Clamp Techniques ; Potassium Channels, Voltage-Gated/chemistry ; Potassium Channels, Voltage-Gated/genetics ; Potassium Channels, Voltage-Gated/metabolism ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Xenopus laevis
    Chemical Substances KCNE1 protein, human ; KCNQ1 Potassium Channel ; KCNQ1 protein, human ; Membrane Proteins ; Potassium Channels, Voltage-Gated ; Recombinant Proteins ; TMC1 protein, human
    Language English
    Publishing date 2019-01-05
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 3116-1
    ISSN 1097-4652 ; 0021-9541
    ISSN (online) 1097-4652
    ISSN 0021-9541
    DOI 10.1002/jcp.28013
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uc I Zs.212: Show issues Location:
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  2. Article ; Online: Emerging concepts in the pharmacogenomics of arrhythmias: ion channel trafficking.

    Harkcom, William T / Abbott, Geoffrey W

    Expert review of cardiovascular therapy

    2010  Volume 8, Issue 8, Page(s) 1161–1173

    Abstract: Continuous, rhythmic beating of the heart requires exquisite control of expression, localization and function of cardiac ion channels - the foundations of the cardiac myocyte action potential. Disruption of any of these processes can alter the shape of ... ...

    Abstract Continuous, rhythmic beating of the heart requires exquisite control of expression, localization and function of cardiac ion channels - the foundations of the cardiac myocyte action potential. Disruption of any of these processes can alter the shape of the action potential, predisposing to cardiac arrhythmias. These arrhythmias can manifest in a variety of ways depending on both the channels involved and the type of disruption (i.e., gain or loss of function). As much as 1% of the population of developed countries is affected by cardiac arrhythmia each year, and a detailed understanding of the mechanism of each arrhythmia is crucial to developing and prescribing the proper therapies. Many of the antiarrhythmic drugs currently on the market were developed before the underlying cause of the arrhythmia was known, and as a result lack specificity, causing side effects. The majority of the available drugs target the conductance of cardiac ion channels, either by blocking or enhancing current through the channel. In recent years, however, it has become apparent that specific targeting of ion channel conductance may not be the most effective means for treatment. Here we review increasing evidence that suggests defects in ion channel trafficking play an important role in the etiology of arrhythmias, and small molecule approaches to correct trafficking defects will likely play an important role in the future of arrhythmia treatment.
    MeSH term(s) Animals ; Anti-Arrhythmia Agents/adverse effects ; Anti-Arrhythmia Agents/pharmacology ; Arrhythmias, Cardiac/drug therapy ; Arrhythmias, Cardiac/physiopathology ; Drug Delivery Systems ; Humans ; Ion Channels/drug effects ; Ion Channels/metabolism ; Pharmacogenetics
    Chemical Substances Anti-Arrhythmia Agents ; Ion Channels
    Language English
    Publishing date 2010-08-28
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2192343-7
    ISSN 1744-8344 ; 1477-9072
    ISSN (online) 1744-8344
    ISSN 1477-9072
    DOI 10.1586/erc.10.89
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 6107: Show issues Location:
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  3. Article: Molecular docking of inhibitors into monoamine oxidase B.

    Harkcom, William T / Bevan, David R

    Biochemical and biophysical research communications

    2007  Volume 360, Issue 2, Page(s) 401–406

    Abstract: Monoamine oxidase B (MAO-B) functions in the deamination of monoamines, including dopamine and norepinephrine. The search for MAO-B inhibitors increased following the discovery that the enzyme may be responsible for generating neurotoxins from various ... ...

    Abstract Monoamine oxidase B (MAO-B) functions in the deamination of monoamines, including dopamine and norepinephrine. The search for MAO-B inhibitors increased following the discovery that the enzyme may be responsible for generating neurotoxins from various endogenous or exogenous compounds. Computational screening methods aid in the search for new inhibitors, but validation studies for specific software packages and receptors are necessary for effective application of these methods. In this study, DOCK 6.0.0 was used to dock a series of inhibitors to MAO-B. Included were studies of re-docking ligands into MAO-B crystal structures, after which a set of 30 compounds with known inhibition constants for MAO-B were docked, including 15 strong inhibitors and 15 weak inhibitors. Good agreement was observed between the top experimental inhibitors and the top ranked docking results, and key interactions between the ligands and receptor were identified.
    MeSH term(s) Binding Sites ; Computer Simulation ; Models, Chemical ; Models, Molecular ; Monoamine Oxidase/chemistry ; Monoamine Oxidase/ultrastructure ; Monoamine Oxidase Inhibitors/chemistry ; Protein Binding ; Sequence Analysis, Protein/methods ; Structure-Activity Relationship
    Chemical Substances Monoamine Oxidase Inhibitors ; Monoamine Oxidase (EC 1.4.3.4)
    Language English
    Publishing date 2007-08-24
    Publishing country United States
    Document type Journal Article
    ZDB-ID 205723-2
    ISSN 0006-291X ; 0006-291X
    ISSN (online) 0006-291X
    ISSN 0006-291X
    DOI 10.1016/j.bbrc.2007.06.055
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 116: Show issues Location:
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  4. Article ; Online: NAD+ and SIRT3 control microtubule dynamics and reduce susceptibility to antimicrotubule agents.

    Harkcom, William T / Ghosh, Ananda K / Sung, Matthew S / Matov, Alexandre / Brown, Kevin D / Giannakakou, Paraskevi / Jaffrey, Samie R

    Proceedings of the National Academy of Sciences of the United States of America

    2014  Volume 111, Issue 24, Page(s) E2443–52

    Abstract: Nicotinamide adenine dinucleotide (NAD(+)) is an endogenous enzyme cofactor and cosubstrate that has effects on diverse cellular and physiologic processes, including reactive oxygen species generation, mitochondrial function, apoptosis, and axonal ... ...

    Abstract Nicotinamide adenine dinucleotide (NAD(+)) is an endogenous enzyme cofactor and cosubstrate that has effects on diverse cellular and physiologic processes, including reactive oxygen species generation, mitochondrial function, apoptosis, and axonal degeneration. A major goal is to identify the NAD(+)-regulated cellular pathways that may mediate these effects. Here we show that the dynamic assembly and disassembly of microtubules is markedly altered by NAD(+). Furthermore, we show that the disassembly of microtubule polymers elicited by microtubule depolymerizing agents is blocked by increasing intracellular NAD(+) levels. We find that these effects of NAD(+) are mediated by the activation of the mitochondrial sirtuin sirtuin-3 (SIRT3). Overexpression of SIRT3 prevents microtubule disassembly and apoptosis elicited by antimicrotubule agents and knockdown of SIRT3 prevents the protective effects of NAD(+) on microtubule polymers. Taken together, these data demonstrate that NAD(+) and SIRT3 regulate microtubule polymerization and the efficacy of antimicrotubule agents.
    MeSH term(s) Animals ; Axons/metabolism ; Colchicine/pharmacology ; Comet Assay ; Cytoskeleton/drug effects ; Cytoskeleton/metabolism ; Ganglia, Spinal/drug effects ; Gene Expression Regulation ; Humans ; MCF-7 Cells ; Microtubules/drug effects ; Microtubules/metabolism ; Mitochondria/metabolism ; NAD/physiology ; Neurons/drug effects ; Nocodazole/pharmacology ; Polymers/chemistry ; Rats ; Reactive Oxygen Species ; Sirtuin 3/physiology ; Tubulin Modulators/pharmacology ; Vinblastine/pharmacology
    Chemical Substances Polymers ; Reactive Oxygen Species ; Tubulin Modulators ; NAD (0U46U6E8UK) ; Vinblastine (5V9KLZ54CY) ; SIRT3 protein, human (EC 3.5.1.-) ; Sirtuin 3 (EC 3.5.1.-) ; Nocodazole (SH1WY3R615) ; Colchicine (SML2Y3J35T)
    Language English
    Publishing date 2014-06-02
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1404269111
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1148: Show issues Location:
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