{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T06:55:59Z","timestamp":1765608959204,"version":"build-2065373602"},"reference-count":69,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T00:00:00Z","timestamp":1672272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health (NIH)","doi-asserted-by":"publisher","award":["5R01HL105239","5U01HL116321"],"award-info":[{"award-number":["5R01HL105239","5U01HL116321"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Mutations in the calcium-sensing protein calmodulin (CaM) 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 CaM 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\u2013contraction coupling in the rat ventricular myocytes to understand how LQT14 variant might give the functional phenotype similar to CPVT4. Changing the CaM-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\u2013contraction coupling was observed above 2 Hz pacing for the mutant CaM. The same conditions applied under beta-adrenergic stimulation led to the rapid onset of arrhythmia in the mutant CaM 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 Ca2+ overload. These simulations provide a mechanistic link to a disease state for LQT14-associated mutations in CaM to yield a CPVT4 phenotype. The results show that small changes to the CaM-regulated inactivation of LCC promote arrhythmia and underscore the significance of CDI in proper heart function.<\/jats:p>","DOI":"10.3390\/biom13010072","type":"journal-article","created":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T03:31:17Z","timestamp":1672371077000},"page":"72","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Understanding Calmodulin Variants Affecting Calcium-Dependent Inactivation of L-Type Calcium Channels through Whole-Cell Simulation of the Cardiac Ventricular Myocyte"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7601-6963","authenticated-orcid":false,"given":"Matthew D.","family":"McCoy","sequence":"first","affiliation":[{"name":"School of Systems Biology, George Mason University, Fairfax, VA 22030, USA"},{"name":"Innovation Center for Biomedical Informatics, Department of Oncology, Georgetown University Medical Center, Georgetown University, Washington, DC 20057, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aman","family":"Ullah","sequence":"additional","affiliation":[{"name":"School of Systems Biology, George Mason University, Fairfax, VA 22030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8488-2180","authenticated-orcid":false,"given":"W. Jonathan","family":"Lederer","sequence":"additional","affiliation":[{"name":"Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 20201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3174-1007","authenticated-orcid":false,"given":"M. Saleet","family":"Jafri","sequence":"additional","affiliation":[{"name":"School of Systems Biology, George Mason University, Fairfax, VA 22030, USA"},{"name":"Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 20201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Chazin, W.J., and Johnson, C.N. (2020). Calmodulin Mutations Associated with Heart Arrhythmia: A Status Report. Int. J. Mol. 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