Functional consequences of changes in the distribution of Ca2+
extrusion pathways between t-tubular and surface membranes in a
model of human ventricular cardiomyocyte

J 2024

Functional consequences of changes in the distribution of Ca2+ extrusion pathways between t-tubular and surface membranes in a model of human ventricular cardiomyocyte

PÁSEK, Michal, Markéta BÉBAROVÁ, Milena ŠIMURDOVÁ and Jiří ŠIMURDA

Basic information

Original name

Functional consequences of changes in the distribution of Ca2+ extrusion pathways between t-tubular and surface membranes in a model of human ventricular cardiomyocyte

Authors

PÁSEK, Michal (203 Czech Republic, belonging to the institution), Markéta BÉBAROVÁ (203 Czech Republic, belonging to the institution), Milena ŠIMURDOVÁ (203 Czech Republic, belonging to the institution) and Jiří ŠIMURDA (203 Czech Republic, belonging to the institution)

Edition

Journal of Molecular and Cellular Cardiology, London, ELSEVIER SCI LTD, 2024, 0022-2828

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30201 Cardiac and Cardiovascular systems

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 5.000 in 2022

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1016/j.yjmcc.2024.06.010

UT WoS

001266902200001

Keywords in English

Human ventricular cell model; T-tubules; Sodium‑calcium exchanger; Calcium ATPase; NCX; PMCA; Membrane protein distribution; Calcium cycling

Abstract

V originále

The sarcolemmal Ca2+ efflux pathways, Na+-Ca2+-exchanger (NCX) and Ca2+-ATPase (PMCA), play a crucial role in the regulation of intracellular Ca2+ load and Ca2+ transient in cardiomyocytes. The distribution of these pathways between the t-tubular and surface membrane of ventricular cardiomyocytes varies between species and is not clear in human. Moreover, several studies suggest that this distribution changes during the development and heart diseases. However, the consequences of NCX and PMCA redistribution in human ventricular cardiomyocytes have not yet been elucidated. In this study, we aimed to address this point by using a mathematical model of the human ventricular myocyte incorporating t-tubules, dyadic spaces, and subsarcolemmal spaces. Effects of various combinations of t-tubular fractions of NCX and PMCA were explored, using values between 0.2 and 1 as reported in animal experiments under normal and pathological conditions. Small variations in the action potential duration (≤ 2%), but significant changes in the peak value of cytosolic Ca2+ transient (up to 17%) were observed at stimulation frequencies corresponding to the human heart rate at rest and during activity. The analysis of model results revealed that the changes in Ca2+ transient induced by redistribution of NCX and PMCA were mainly caused by alterations in Ca2+ concentrations in the subsarcolemmal spaces and cytosol during the diastolic phase of the stimulation cycle. The results suggest that redistribution of both transporters between the t-tubular and surface membranes contributes to changes in contractility in human ventricular cardiomyocytes during their development and heart disease and may promote arrhythmogenesis.

Links

NU22-02-00348, research and development project

Name: Funkční hodnocení genetických variant u případů klinicky „skutečné“ idiopatické fibrilace komor: in vitro a in silico modelování s cílem odhalit arytmogenní mechanismus

Investor: Ministry of Health of the CR, Subprogram 1 - standard

Citovat

PÁSEK, Michal, Markéta BÉBAROVÁ, Milena ŠIMURDOVÁ and Jiří ŠIMURDA. Functional consequences of changes in the distribution of Ca2+ extrusion pathways between t-tubular and surface membranes in a model of human ventricular cardiomyocyte. Journal of Molecular and Cellular Cardiology. London: ELSEVIER SCI LTD, 2024, vol. 193, August 2024, p. 113-124. ISSN 0022-2828. Available from: https://dx.doi.org/10.1016/j.yjmcc.2024.06.010.

@article{2418614,
   author = {Pásek, Michal and Bébarová, Markéta and Šimurdová, Milena and Šimurda, Jiří},
   article_location = {London},
   article_number = {August 2024},
   doi = {http://dx.doi.org/10.1016/j.yjmcc.2024.06.010},
   keywords = {Human ventricular cell model; T-tubules; Sodium‑calcium exchanger; Calcium ATPase; NCX; PMCA; Membrane protein distribution; Calcium cycling},
   language = {eng},
   issn = {0022-2828},
   journal = {Journal of Molecular and Cellular Cardiology},
   title = {Functional consequences of changes in the distribution of Ca2+ extrusion pathways between t-tubular and surface membranes in a model of human ventricular cardiomyocyte},
   url = {https://www.sciencedirect.com/science/article/pii/S002228282400107X?via%3Dihub},
   volume = {193},
   year = {2024}
}

TY  - JOUR
ID  - 2418614
AU  - Pásek, Michal - Bébarová, Markéta - Šimurdová, Milena - Šimurda, Jiří
PY  - 2024
TI  - Functional consequences of changes in the distribution of Ca2+ extrusion pathways between t-tubular and surface membranes in a model of human ventricular cardiomyocyte
JF  - Journal of Molecular and Cellular Cardiology
VL  - 193
IS  - August 2024
SP  - 113-124
EP  - 113-124
PB  - ELSEVIER SCI LTD
SN  - 00222828
KW  - Human ventricular cell model
KW  - T-tubules
KW  - Sodium‑calcium exchanger
KW  - Calcium ATPase
KW  - NCX
KW  - PMCA
KW  - Membrane protein distribution
KW  - Calcium cycling
UR  - https://www.sciencedirect.com/science/article/pii/S002228282400107X?via%3Dihub
N2  - The sarcolemmal Ca2+ efflux pathways, Na+-Ca2+-exchanger (NCX) and Ca2+-ATPase (PMCA), play a crucial role in the regulation of intracellular Ca2+ load and Ca2+ transient in cardiomyocytes. The distribution of these pathways between the t-tubular and surface membrane of ventricular cardiomyocytes varies between species and is not clear in human. Moreover, several studies suggest that this distribution changes during the development and heart diseases. However, the consequences of NCX and PMCA redistribution in human ventricular cardiomyocytes have not yet been elucidated. In this study, we aimed to address this point by using a mathematical model of the human ventricular myocyte incorporating t-tubules, dyadic spaces, and subsarcolemmal spaces. Effects of various combinations of t-tubular fractions of NCX and PMCA were explored, using values between 0.2 and 1 as reported in animal experiments under normal and pathological conditions. Small variations in the action potential duration (≤ 2%), but significant changes in the peak value of cytosolic Ca2+ transient (up to 17%) were observed at stimulation frequencies corresponding to the human heart rate at rest and during activity. The analysis of model results revealed that the changes in Ca2+ transient induced by redistribution of NCX and PMCA were mainly caused by alterations in Ca2+ concentrations in the subsarcolemmal spaces and cytosol during the diastolic phase of the stimulation cycle. The results suggest that redistribution of both transporters between the t-tubular and surface membranes contributes to changes in contractility in human ventricular cardiomyocytes during their development and heart disease and may promote arrhythmogenesis.
ER  -

PÁSEK, Michal, Markéta BÉBAROVÁ, Milena ŠIMURDOVÁ and Jiří ŠIMURDA. Functional consequences of changes in the distribution of Ca2+ extrusion pathways between t-tubular and surface membranes in a model of human ventricular cardiomyocyte. \textit{Journal of Molecular and Cellular Cardiology}. London: ELSEVIER SCI LTD, 2024, vol.~193, August 2024, p.~113-124. ISSN~0022-2828. Available from: https://dx.doi.org/10.1016/j.yjmcc.2024.06.010.

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