Recording ten-fold larger I Kr conductances with automated patch clamping using equimolar Cs + solutions
The rapid delayed rectifier potassium current (I ) is important for cardiac repolarization and is most often involved in drug-induced arrhythmias. However, accurately measuring this current can be challenging in human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes because of its small...
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Published in | Frontiers in physiology Vol. 15; p. 1298340 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Switzerland
2024
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Subjects | |
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Abstract | The rapid delayed rectifier potassium current (I
) is important for cardiac repolarization and is most often involved in drug-induced arrhythmias. However, accurately measuring this current can be challenging in human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes because of its small current density. Interestingly, the ion channel conducting I
, hERG channel, is not only permeable to K
ions but also to Cs
ions when present in equimolar concentrations inside and outside of the cell.
In this study, I
was measured from Chinese hamster ovary (CHO)-hERG cells and hiPSC-CM using either Cs
or K
as the charge carrier. Equimolar Cs
has been used in the literature in manual patch-clamp experiments, and here, we apply this approach using automated patch-clamp systems. Four different (pre)clinical drugs were tested to compare their effects on Cs
- and K
-based currents.
Using equimolar Cs
solutions gave rise to approximately ten-fold larger hERG conductances. Comparison of Cs
- and K
-mediated currents upon application of dofetilide, desipramine, moxifloxacin, or LUF7244 revealed many similarities in inhibition or activation properties of the drugs studied. Using equimolar Cs
solutions gave rise to approximately ten-fold larger hERG conductances. In hiPSC-CM, the Cs
-based conductance is larger compared to the known K
-based conductance, and the Cs
hERG conductance can be inhibited similarly to the K
-based conductance.
Using equimolar Cs
instead of K
for I
measurements in an automated patch-clamp system gives rise to a new method by which, for example, quick scans can be performed on effects of drugs on hERG currents. This application is specifically relevant when such experiments are performed using cells which express small I
current densities in combination with small membrane capacitances. |
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AbstractList | The rapid delayed rectifier potassium current (I
) is important for cardiac repolarization and is most often involved in drug-induced arrhythmias. However, accurately measuring this current can be challenging in human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes because of its small current density. Interestingly, the ion channel conducting I
, hERG channel, is not only permeable to K
ions but also to Cs
ions when present in equimolar concentrations inside and outside of the cell.
In this study, I
was measured from Chinese hamster ovary (CHO)-hERG cells and hiPSC-CM using either Cs
or K
as the charge carrier. Equimolar Cs
has been used in the literature in manual patch-clamp experiments, and here, we apply this approach using automated patch-clamp systems. Four different (pre)clinical drugs were tested to compare their effects on Cs
- and K
-based currents.
Using equimolar Cs
solutions gave rise to approximately ten-fold larger hERG conductances. Comparison of Cs
- and K
-mediated currents upon application of dofetilide, desipramine, moxifloxacin, or LUF7244 revealed many similarities in inhibition or activation properties of the drugs studied. Using equimolar Cs
solutions gave rise to approximately ten-fold larger hERG conductances. In hiPSC-CM, the Cs
-based conductance is larger compared to the known K
-based conductance, and the Cs
hERG conductance can be inhibited similarly to the K
-based conductance.
Using equimolar Cs
instead of K
for I
measurements in an automated patch-clamp system gives rise to a new method by which, for example, quick scans can be performed on effects of drugs on hERG currents. This application is specifically relevant when such experiments are performed using cells which express small I
current densities in combination with small membrane capacitances. |
Author | Voigt, Niels Seibertz, Fitzwilliam Bloothooft, Meye Verbruggen, Bente van der Heyden, Marcel A G de Boer, Teun P |
Author_xml | – sequence: 1 givenname: Meye surname: Bloothooft fullname: Bloothooft, Meye organization: Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands – sequence: 2 givenname: Bente surname: Verbruggen fullname: Verbruggen, Bente organization: Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands – sequence: 3 givenname: Fitzwilliam surname: Seibertz fullname: Seibertz, Fitzwilliam organization: Nanion Technologies GmbH, Munich, Germany – sequence: 4 givenname: Marcel A G surname: van der Heyden fullname: van der Heyden, Marcel A G organization: Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands – sequence: 5 givenname: Niels surname: Voigt fullname: Voigt, Niels organization: Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany – sequence: 6 givenname: Teun P surname: de Boer fullname: de Boer, Teun P organization: Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands |
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Title | Recording ten-fold larger I Kr conductances with automated patch clamping using equimolar Cs + solutions |
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