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A model for cooperative gating of L-type Ca(2+) channels and its effects on cardiac alternans dynamics

In ventricular myocytes, membrane depolarization during the action potential (AP) causes synchronous activation of multiple L-type Ca(V)1.2 channels (LTCCs), which trigger the release of calcium (Ca(2+)) from the sarcoplasmic reticulum (SR). This results in an increase in intracellular Ca(2+) (Ca(i)...

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Autores principales: Sato, Daisuke, Dixon, Rose E., Santana, Luis F., Navedo, Manuel F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786340/
https://www.ncbi.nlm.nih.gov/pubmed/29338006
http://dx.doi.org/10.1371/journal.pcbi.1005906
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author Sato, Daisuke
Dixon, Rose E.
Santana, Luis F.
Navedo, Manuel F.
author_facet Sato, Daisuke
Dixon, Rose E.
Santana, Luis F.
Navedo, Manuel F.
author_sort Sato, Daisuke
collection PubMed
description In ventricular myocytes, membrane depolarization during the action potential (AP) causes synchronous activation of multiple L-type Ca(V)1.2 channels (LTCCs), which trigger the release of calcium (Ca(2+)) from the sarcoplasmic reticulum (SR). This results in an increase in intracellular Ca(2+) (Ca(i)) that initiates contraction. During pulsus alternans, cardiac contraction is unstable, going from weak to strong in successive beats despite a constant heart rate. These cardiac alternans can be caused by the instability of membrane potential (V(m)) due to steep AP duration (APD) restitution (V(m)-driven alternans), instability of Ca(i) cycling (Ca(2+)-driven alternans), or both, and may be modulated by functional coupling between clustered Ca(V)1.2 (e.g. cooperative gating). Here, mathematical analysis and computational models were used to determine how changes in the strength of cooperative gating between LTCCs may impact membrane voltage and intracellular Ca(2+) dynamics in the heart. We found that increasing the degree of coupling between LTCCs increases the amplitude of Ca(2+) currents (I(CaL)) and prolongs AP duration (APD). Increased AP duration is known to promote cardiac alternans, a potentially arrhythmogenic substrate. In addition, our analysis shows that increasing the strength of cooperative activation of LTCCs makes the coupling of Ca(2+) on the membrane voltage (Ca(i)→V(m) coupling) more positive and destabilizes the V(m)-Ca(i) dynamics for V(m)-driven alternans and Ca(i)-driven alternans, but not for quasiperiodic oscillation. These results suggest that cooperative gating of LTCCs may have a major impact on cardiac excitation-contraction coupling, not only by prolonging APD, but also by altering Ca(i)→V(m) coupling and potentially promoting cardiac arrhythmias.
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spelling pubmed-57863402018-02-09 A model for cooperative gating of L-type Ca(2+) channels and its effects on cardiac alternans dynamics Sato, Daisuke Dixon, Rose E. Santana, Luis F. Navedo, Manuel F. PLoS Comput Biol Research Article In ventricular myocytes, membrane depolarization during the action potential (AP) causes synchronous activation of multiple L-type Ca(V)1.2 channels (LTCCs), which trigger the release of calcium (Ca(2+)) from the sarcoplasmic reticulum (SR). This results in an increase in intracellular Ca(2+) (Ca(i)) that initiates contraction. During pulsus alternans, cardiac contraction is unstable, going from weak to strong in successive beats despite a constant heart rate. These cardiac alternans can be caused by the instability of membrane potential (V(m)) due to steep AP duration (APD) restitution (V(m)-driven alternans), instability of Ca(i) cycling (Ca(2+)-driven alternans), or both, and may be modulated by functional coupling between clustered Ca(V)1.2 (e.g. cooperative gating). Here, mathematical analysis and computational models were used to determine how changes in the strength of cooperative gating between LTCCs may impact membrane voltage and intracellular Ca(2+) dynamics in the heart. We found that increasing the degree of coupling between LTCCs increases the amplitude of Ca(2+) currents (I(CaL)) and prolongs AP duration (APD). Increased AP duration is known to promote cardiac alternans, a potentially arrhythmogenic substrate. In addition, our analysis shows that increasing the strength of cooperative activation of LTCCs makes the coupling of Ca(2+) on the membrane voltage (Ca(i)→V(m) coupling) more positive and destabilizes the V(m)-Ca(i) dynamics for V(m)-driven alternans and Ca(i)-driven alternans, but not for quasiperiodic oscillation. These results suggest that cooperative gating of LTCCs may have a major impact on cardiac excitation-contraction coupling, not only by prolonging APD, but also by altering Ca(i)→V(m) coupling and potentially promoting cardiac arrhythmias. Public Library of Science 2018-01-16 /pmc/articles/PMC5786340/ /pubmed/29338006 http://dx.doi.org/10.1371/journal.pcbi.1005906 Text en © 2018 Sato et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Sato, Daisuke
Dixon, Rose E.
Santana, Luis F.
Navedo, Manuel F.
A model for cooperative gating of L-type Ca(2+) channels and its effects on cardiac alternans dynamics
title A model for cooperative gating of L-type Ca(2+) channels and its effects on cardiac alternans dynamics
title_full A model for cooperative gating of L-type Ca(2+) channels and its effects on cardiac alternans dynamics
title_fullStr A model for cooperative gating of L-type Ca(2+) channels and its effects on cardiac alternans dynamics
title_full_unstemmed A model for cooperative gating of L-type Ca(2+) channels and its effects on cardiac alternans dynamics
title_short A model for cooperative gating of L-type Ca(2+) channels and its effects on cardiac alternans dynamics
title_sort model for cooperative gating of l-type ca(2+) channels and its effects on cardiac alternans dynamics
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786340/
https://www.ncbi.nlm.nih.gov/pubmed/29338006
http://dx.doi.org/10.1371/journal.pcbi.1005906
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