Functional consequences of different distribution of NCX and PMCA between t-tubular and surface membranes in a model of the human ventricular cardiomyocyte

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14110%2F23%3A00134666" target="_blank" >RIV/00216224:14110/23:00134666 - isvavai.cz</a>

Result on the web

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DOI - Digital Object Identifier

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Result language

angličtina

Original language name

Functional consequences of different distribution of NCX and PMCA between t-tubular and surface membranes in a model of the human ventricular cardiomyocyte

Original language description

Background: 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. Experimental studies published so far have indicated that the t-tubular fractions of NCX and PMCA (fNaCa,t and fpCa,t) in ventricular myocytes might be lower than 0.3 as well as higher than 0.9. Moreover, the membrane distribution of both transporters appears to vary during development and cardiac diseases. However, the consequences of changes in NCX and PMCA distribution between the t-tubular and surface membranes of human ventricular cardiomyocytes have not yet been elucidated. Methods: We addressed 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 fNaCa,t and fpCa,t were explored using values between 0.2 and 1 as reported in animal experiments under normal and pathological conditions. For numerical solution, the computational software MATLAB version 7.2 (MathWorks, Natick, MA, USA) was used. Results: Small variations in the duration of action potentials (≤ 2%), but a substantial increase in the peak value of cytosolic Ca2+ transient (up to 18%) were observed in the model when NCX and PMCA were redistributed to the t-tubular or surface membranes. This effect was caused by an increase of Ca2+ load in the sarcoplasmic reticulum due to an increase of Ca2+ concentration in the cytosol (after the termination of Ca2+ transient) in response to the reduced activity of NCX and PMCA under the membrane domain where these transporters predominated. Conclusion: These results indicate that redistribution of both transporters between the t-tubular and surface membranes may contribute to the changes in the inotropic state of human ventricular cardiomyocytes during their development as well as during cardiac diseases.

Czech name

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Czech description

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Type

O - Miscellaneous

CEP classification

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OECD FORD branch

30201 - Cardiac and Cardiovascular systems

Project

<a href="/en/project/NU22-02-00348" target="_blank" >NU22-02-00348: Functional assessment of genetic variants in clinically “true” cases of idiopathic ventricular fibrillation: in vitro and in silico modelling to reveal the arrhythmogenic mechanism</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2023

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů