Understanding Calmodulin Variants Affecting Calcium-Dependent Inactivation of L-Type Calcium Channels through Whole-Cell Simulation of the Cardiac Ventricular Myocyte
Mutations in the calcium-sensing protein calmodulin (<i>CaM</i>) have been linked to two cardiac arrhythmia diseases, Long QT Syndrome 14 (LQT14) and Catecholaminergic Polymorphic Ventricular Tachycardia Type 4 (CPVT4), with varying degrees of severity. Functional characterization of the...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-12-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/13/1/72 |
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| author | Matthew D. McCoy Aman Ullah W. Jonathan Lederer M. Saleet Jafri |
| author_facet | Matthew D. McCoy Aman Ullah W. Jonathan Lederer M. Saleet Jafri |
| author_sort | Matthew D. McCoy |
| collection | DOAJ |
| description | Mutations in the calcium-sensing protein calmodulin (<i>CaM</i>) have been linked to two cardiac arrhythmia diseases, Long QT Syndrome 14 (LQT14) and Catecholaminergic Polymorphic Ventricular Tachycardia Type 4 (CPVT4), with varying degrees of severity. Functional characterization of the <i>CaM</i> mutants most strongly associated with LQT14 show a clear disruption of the calcium-dependent inactivation (CDI) of the L-Type calcium channel (LCC). CPVT4 mutants on the other hand are associated with changes in their affinity to the ryanodine receptor. In clinical studies, some variants have been associated with both CPVT4 and LQT15. This study uses simulations in a model for excitation–contraction coupling in the rat ventricular myocytes to understand how LQT14 variant might give the functional phenotype similar to CPVT4. Changing the <i>CaM</i>-dependent transition rate by a factor of 0.75 corresponding to the D96V variant and by a factor of 0.90 corresponding to the F142L or N98S variants, in a physiologically based stochastic model of the LCC prolonger, the action potential duration changed by a small amount in a cardiac myocyte but did not disrupt CICR at 1, 2, and 4 Hz. Under beta-adrenergic simulation abnormal excitation–contraction coupling was observed above 2 Hz pacing for the mutant <i>CaM</i>. The same conditions applied under beta-adrenergic stimulation led to the rapid onset of arrhythmia in the mutant <i>CaM</i> simulations. Simulations with the LQT14 mutations under the conditions of rapid pacing with beta-adrenergic stimulation drives the cardiac myocyte toward an arrhythmic state known as Ca<sup>2+</sup> overload. These simulations provide a mechanistic link to a disease state for LQT14-associated mutations in <i>CaM</i> to yield a CPVT4 phenotype. The results show that small changes to the <i>CaM</i>-regulated inactivation of LCC promote arrhythmia and underscore the significance of CDI in proper heart function. |
| first_indexed | 2024-03-09T13:27:32Z |
| format | Article |
| id | doaj.art-ae2c54ff9bf54e888602cb1867c65c1b |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T13:27:32Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-ae2c54ff9bf54e888602cb1867c65c1b2023-11-30T21:22:19ZengMDPI AGBiomolecules2218-273X2022-12-011317210.3390/biom13010072Understanding Calmodulin Variants Affecting Calcium-Dependent Inactivation of L-Type Calcium Channels through Whole-Cell Simulation of the Cardiac Ventricular MyocyteMatthew D. McCoy0Aman Ullah1W. Jonathan Lederer2M. Saleet Jafri3School of Systems Biology, George Mason University, Fairfax, VA 22030, USASchool of Systems Biology, George Mason University, Fairfax, VA 22030, USACenter for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 20201, USASchool of Systems Biology, George Mason University, Fairfax, VA 22030, USAMutations in the calcium-sensing protein calmodulin (<i>CaM</i>) have been linked to two cardiac arrhythmia diseases, Long QT Syndrome 14 (LQT14) and Catecholaminergic Polymorphic Ventricular Tachycardia Type 4 (CPVT4), with varying degrees of severity. Functional characterization of the <i>CaM</i> mutants most strongly associated with LQT14 show a clear disruption of the calcium-dependent inactivation (CDI) of the L-Type calcium channel (LCC). CPVT4 mutants on the other hand are associated with changes in their affinity to the ryanodine receptor. In clinical studies, some variants have been associated with both CPVT4 and LQT15. This study uses simulations in a model for excitation–contraction coupling in the rat ventricular myocytes to understand how LQT14 variant might give the functional phenotype similar to CPVT4. Changing the <i>CaM</i>-dependent transition rate by a factor of 0.75 corresponding to the D96V variant and by a factor of 0.90 corresponding to the F142L or N98S variants, in a physiologically based stochastic model of the LCC prolonger, the action potential duration changed by a small amount in a cardiac myocyte but did not disrupt CICR at 1, 2, and 4 Hz. Under beta-adrenergic simulation abnormal excitation–contraction coupling was observed above 2 Hz pacing for the mutant <i>CaM</i>. The same conditions applied under beta-adrenergic stimulation led to the rapid onset of arrhythmia in the mutant <i>CaM</i> simulations. Simulations with the LQT14 mutations under the conditions of rapid pacing with beta-adrenergic stimulation drives the cardiac myocyte toward an arrhythmic state known as Ca<sup>2+</sup> overload. These simulations provide a mechanistic link to a disease state for LQT14-associated mutations in <i>CaM</i> to yield a CPVT4 phenotype. The results show that small changes to the <i>CaM</i>-regulated inactivation of LCC promote arrhythmia and underscore the significance of CDI in proper heart function.https://www.mdpi.com/2218-273X/13/1/72CPVT4LQT14calmodulinarrhythmiaheartLQT |
| spellingShingle | Matthew D. McCoy Aman Ullah W. Jonathan Lederer M. Saleet Jafri Understanding Calmodulin Variants Affecting Calcium-Dependent Inactivation of L-Type Calcium Channels through Whole-Cell Simulation of the Cardiac Ventricular Myocyte Biomolecules CPVT4 LQT14 calmodulin arrhythmia heart LQT |
| title | Understanding Calmodulin Variants Affecting Calcium-Dependent Inactivation of L-Type Calcium Channels through Whole-Cell Simulation of the Cardiac Ventricular Myocyte |
| title_full | Understanding Calmodulin Variants Affecting Calcium-Dependent Inactivation of L-Type Calcium Channels through Whole-Cell Simulation of the Cardiac Ventricular Myocyte |
| title_fullStr | Understanding Calmodulin Variants Affecting Calcium-Dependent Inactivation of L-Type Calcium Channels through Whole-Cell Simulation of the Cardiac Ventricular Myocyte |
| title_full_unstemmed | Understanding Calmodulin Variants Affecting Calcium-Dependent Inactivation of L-Type Calcium Channels through Whole-Cell Simulation of the Cardiac Ventricular Myocyte |
| title_short | Understanding Calmodulin Variants Affecting Calcium-Dependent Inactivation of L-Type Calcium Channels through Whole-Cell Simulation of the Cardiac Ventricular Myocyte |
| title_sort | understanding calmodulin variants affecting calcium dependent inactivation of l type calcium channels through whole cell simulation of the cardiac ventricular myocyte |
| topic | CPVT4 LQT14 calmodulin arrhythmia heart LQT |
| url | https://www.mdpi.com/2218-273X/13/1/72 |
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