Dynamic Current Clamp Experiments Define the Functional Roles of I K1 and I to,f in Human Induced Pluripotent Stem Cell Derived Cardiomyocytes
Year: 2017
Type: preprint
Abstract: The transient outward potassium current ( I to ) plays a key, albeit incompletely defined, role in cardiomyocyte physiology and pathophysiology. In light of the technical challenges of studying adult human cardiomyocytes, this study examines the use of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) as a system which potentially preserves the native cellular milieu of human cardiomyocytes. ISPC-CMs express a robust I to with slow recovery kinetics and fail to express the rapidly recovering I to,f which is implicated in human disease. Overexpression of the accessory subunit KChIP2 (which is not expressed in iPSC-CMs) resulted in restoration of a rapid component of recovery. To define the functional role of I to , dynamic current clamp was used to introduce computationally modeled currents into iPSC-CMs while recording action potentials. However, iPSC-CMs exhibit action potentials with multiple immature physiological properties, including slow upstroke velocity, heterogeneous action potential waveforms, and the absence of a phase 1 notch, thus potentially limiting the utility of these cells as a model of adult cardiomyocytes. Importantly, the introduction of modeled inwardly rectified current ( I K1 ) ameliorated these immature properties by restoring a hyperpolarized resting membrane potential. In this context of normalized action potential morphologies, dynamic current clamp experiments introducing I to,f demonstrated that there is significant cell-to-cell heterogeneity and that the functional effect of I to,f is highly sensitive to the action potential plateau voltage in each cell.
DOI: 10.1101/135400
Authors: Scott B. Marrus, Steven Springer, Eric Johnson, Rita J. Martinez, Edward J. Dranoff, Rebecca Mellor, Kathryn Yamada
Institution: Washington University in St. Louis
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2613611573