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Adrenergic Stress Protection of Human iPS Cell-Derived Cardiomyocytes by Fast K(v)7.1 Recycling

The fight-or-flight response (FFR), a physiological acute stress reaction, involves positive chronotropic and inotropic effects on heart muscle cells mediated through β-adrenoceptor activation. Increased systolic calcium is required to enable stronger heart contractions whereas elevated potassium cu...

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Autores principales: Piccini, Ilaria, Fehrmann, Edda, Frank, Stefan, Müller, Frank U., Greber, Boris, Seebohm, Guiscard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603700/
https://www.ncbi.nlm.nih.gov/pubmed/28959214
http://dx.doi.org/10.3389/fphys.2017.00705
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author Piccini, Ilaria
Fehrmann, Edda
Frank, Stefan
Müller, Frank U.
Greber, Boris
Seebohm, Guiscard
author_facet Piccini, Ilaria
Fehrmann, Edda
Frank, Stefan
Müller, Frank U.
Greber, Boris
Seebohm, Guiscard
author_sort Piccini, Ilaria
collection PubMed
description The fight-or-flight response (FFR), a physiological acute stress reaction, involves positive chronotropic and inotropic effects on heart muscle cells mediated through β-adrenoceptor activation. Increased systolic calcium is required to enable stronger heart contractions whereas elevated potassium currents are to limit the duration of the action potentials and prevent arrhythmia. The latter effect is accomplished by an increased functional activity of the K(v)7.1 channel encoded by KCNQ1. Current knowledge, however, does not sufficiently explain the full extent of rapid K(v)7.1 activation and may hence be incomplete. Using inducible genetic KCNQ1 complementation in KCNQ1-deficient human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we here reinvestigate the functional role of K(v)7.1 in adapting human CMs to adrenergic stress. Under baseline conditions, K(v)7.1 was barely detectable at the plasma membrane of hiPSC-CMs, yet it fully protected these from adrenergic stress-induced beat-to-beat variability of repolarization and torsade des pointes-like arrhythmia. Furthermore, isoprenaline treatment increased field potential durations specifically in KCNQ1-deficient CMs to cause these adverse macroscopic effects. Mechanistically, we find that the protective action by K(v)7.1 resides in a rapid translocation of channel proteins from intracellular stores to the plasma membrane, induced by adrenergic signaling. Gene silencing experiments targeting RAB GTPases, mediators of intracellular vesicle trafficking, showed that fast K(v)7.1 recycling under acute stress conditions is RAB4A-dependent.Our data reveal a key mechanism underlying the rapid adaptation of human cardiomyocytes to adrenergic stress. These findings moreover aid to the understanding of disease pathology in long QT syndrome and bear important implications for safety pharmacological screening.
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spelling pubmed-56037002017-09-28 Adrenergic Stress Protection of Human iPS Cell-Derived Cardiomyocytes by Fast K(v)7.1 Recycling Piccini, Ilaria Fehrmann, Edda Frank, Stefan Müller, Frank U. Greber, Boris Seebohm, Guiscard Front Physiol Physiology The fight-or-flight response (FFR), a physiological acute stress reaction, involves positive chronotropic and inotropic effects on heart muscle cells mediated through β-adrenoceptor activation. Increased systolic calcium is required to enable stronger heart contractions whereas elevated potassium currents are to limit the duration of the action potentials and prevent arrhythmia. The latter effect is accomplished by an increased functional activity of the K(v)7.1 channel encoded by KCNQ1. Current knowledge, however, does not sufficiently explain the full extent of rapid K(v)7.1 activation and may hence be incomplete. Using inducible genetic KCNQ1 complementation in KCNQ1-deficient human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we here reinvestigate the functional role of K(v)7.1 in adapting human CMs to adrenergic stress. Under baseline conditions, K(v)7.1 was barely detectable at the plasma membrane of hiPSC-CMs, yet it fully protected these from adrenergic stress-induced beat-to-beat variability of repolarization and torsade des pointes-like arrhythmia. Furthermore, isoprenaline treatment increased field potential durations specifically in KCNQ1-deficient CMs to cause these adverse macroscopic effects. Mechanistically, we find that the protective action by K(v)7.1 resides in a rapid translocation of channel proteins from intracellular stores to the plasma membrane, induced by adrenergic signaling. Gene silencing experiments targeting RAB GTPases, mediators of intracellular vesicle trafficking, showed that fast K(v)7.1 recycling under acute stress conditions is RAB4A-dependent.Our data reveal a key mechanism underlying the rapid adaptation of human cardiomyocytes to adrenergic stress. These findings moreover aid to the understanding of disease pathology in long QT syndrome and bear important implications for safety pharmacological screening. Frontiers Media S.A. 2017-09-14 /pmc/articles/PMC5603700/ /pubmed/28959214 http://dx.doi.org/10.3389/fphys.2017.00705 Text en Copyright © 2017 Piccini, Fehrmann, Frank, Müller, Greber and Seebohm. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Piccini, Ilaria
Fehrmann, Edda
Frank, Stefan
Müller, Frank U.
Greber, Boris
Seebohm, Guiscard
Adrenergic Stress Protection of Human iPS Cell-Derived Cardiomyocytes by Fast K(v)7.1 Recycling
title Adrenergic Stress Protection of Human iPS Cell-Derived Cardiomyocytes by Fast K(v)7.1 Recycling
title_full Adrenergic Stress Protection of Human iPS Cell-Derived Cardiomyocytes by Fast K(v)7.1 Recycling
title_fullStr Adrenergic Stress Protection of Human iPS Cell-Derived Cardiomyocytes by Fast K(v)7.1 Recycling
title_full_unstemmed Adrenergic Stress Protection of Human iPS Cell-Derived Cardiomyocytes by Fast K(v)7.1 Recycling
title_short Adrenergic Stress Protection of Human iPS Cell-Derived Cardiomyocytes by Fast K(v)7.1 Recycling
title_sort adrenergic stress protection of human ips cell-derived cardiomyocytes by fast k(v)7.1 recycling
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603700/
https://www.ncbi.nlm.nih.gov/pubmed/28959214
http://dx.doi.org/10.3389/fphys.2017.00705
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