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Identifying Drug Response by Combining Measurements of the Membrane Potential, the Cytosolic Calcium Concentration, and the Extracellular Potential in Microphysiological Systems

Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) offer a new means to study and understand the human cardiac action potential, and can give key insight into how compounds may interact with important molecular pathways to destabilize the electrical function of the heart. I...

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Autores principales: Jæger, Karoline Horgmo, Charwat, Verena, Wall, Samuel, Healy, Kevin E., Tveito, Aslak
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898238/
https://www.ncbi.nlm.nih.gov/pubmed/33628168
http://dx.doi.org/10.3389/fphar.2020.569489
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author Jæger, Karoline Horgmo
Charwat, Verena
Wall, Samuel
Healy, Kevin E.
Tveito, Aslak
author_facet Jæger, Karoline Horgmo
Charwat, Verena
Wall, Samuel
Healy, Kevin E.
Tveito, Aslak
author_sort Jæger, Karoline Horgmo
collection PubMed
description Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) offer a new means to study and understand the human cardiac action potential, and can give key insight into how compounds may interact with important molecular pathways to destabilize the electrical function of the heart. Important features of the action potential can be readily measured using standard experimental techniques, such as the use of voltage sensitive dyes and fluorescent genetic reporters to estimate transmembrane potentials and cytosolic calcium concentrations. Using previously introduced computational procedures, such measurements can be used to estimate the current density of major ion channels present in hiPSC-CMs, and how compounds may alter their behavior. However, due to the limitations of optical recordings, resolving the sodium current remains difficult from these data. Here we show that if these optical measurements are complemented with observations of the extracellular potential using multi electrode arrays (MEAs), we can accurately estimate the current density of the sodium channels. This inversion of the sodium current relies on observation of the conduction velocity which turns out to be straightforwardly computed using measurements of extracellular waves across the electrodes. The combined data including the membrane potential, the cytosolic calcium concentration and the extracellular potential further opens up for the possibility of accurately estimating the effect of novel drugs applied to hiPSC-CMs.
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spelling pubmed-78982382021-02-23 Identifying Drug Response by Combining Measurements of the Membrane Potential, the Cytosolic Calcium Concentration, and the Extracellular Potential in Microphysiological Systems Jæger, Karoline Horgmo Charwat, Verena Wall, Samuel Healy, Kevin E. Tveito, Aslak Front Pharmacol Pharmacology Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) offer a new means to study and understand the human cardiac action potential, and can give key insight into how compounds may interact with important molecular pathways to destabilize the electrical function of the heart. Important features of the action potential can be readily measured using standard experimental techniques, such as the use of voltage sensitive dyes and fluorescent genetic reporters to estimate transmembrane potentials and cytosolic calcium concentrations. Using previously introduced computational procedures, such measurements can be used to estimate the current density of major ion channels present in hiPSC-CMs, and how compounds may alter their behavior. However, due to the limitations of optical recordings, resolving the sodium current remains difficult from these data. Here we show that if these optical measurements are complemented with observations of the extracellular potential using multi electrode arrays (MEAs), we can accurately estimate the current density of the sodium channels. This inversion of the sodium current relies on observation of the conduction velocity which turns out to be straightforwardly computed using measurements of extracellular waves across the electrodes. The combined data including the membrane potential, the cytosolic calcium concentration and the extracellular potential further opens up for the possibility of accurately estimating the effect of novel drugs applied to hiPSC-CMs. Frontiers Media S.A. 2021-02-08 /pmc/articles/PMC7898238/ /pubmed/33628168 http://dx.doi.org/10.3389/fphar.2020.569489 Text en Copyright © 2021 Jæger, Charwat, Wall, Healy and Tveito. 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) and the copyright owner(s) 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 Pharmacology
Jæger, Karoline Horgmo
Charwat, Verena
Wall, Samuel
Healy, Kevin E.
Tveito, Aslak
Identifying Drug Response by Combining Measurements of the Membrane Potential, the Cytosolic Calcium Concentration, and the Extracellular Potential in Microphysiological Systems
title Identifying Drug Response by Combining Measurements of the Membrane Potential, the Cytosolic Calcium Concentration, and the Extracellular Potential in Microphysiological Systems
title_full Identifying Drug Response by Combining Measurements of the Membrane Potential, the Cytosolic Calcium Concentration, and the Extracellular Potential in Microphysiological Systems
title_fullStr Identifying Drug Response by Combining Measurements of the Membrane Potential, the Cytosolic Calcium Concentration, and the Extracellular Potential in Microphysiological Systems
title_full_unstemmed Identifying Drug Response by Combining Measurements of the Membrane Potential, the Cytosolic Calcium Concentration, and the Extracellular Potential in Microphysiological Systems
title_short Identifying Drug Response by Combining Measurements of the Membrane Potential, the Cytosolic Calcium Concentration, and the Extracellular Potential in Microphysiological Systems
title_sort identifying drug response by combining measurements of the membrane potential, the cytosolic calcium concentration, and the extracellular potential in microphysiological systems
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898238/
https://www.ncbi.nlm.nih.gov/pubmed/33628168
http://dx.doi.org/10.3389/fphar.2020.569489
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