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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)...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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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. |
format | Online Article Text |
id | pubmed-5786340 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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