{"title":"Analysis of Slow Inactivation of Nav1.5 Channels in the Development of Hereditary Heart Pathology","authors":"A. K. Zaitseva, K. I. Perepelina, A. A. Kostareva","doi":"10.1134/s1990519x24700263","DOIUrl":null,"url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Abstract</h3><p>Cardiac voltage-gated Na<sub>v</sub>1.5 sodium channels are responsible for initiation and propagation of action potentials in cardiomyocytes. Na<sub>v</sub>1.5 dysfunction may be due to both pathogenic variants in the gene itself <i>SCN5A</i>, encoding Na<sub>v</sub>1.5, and genetic variants in the genes of other proteins that regulate its activity and transport. The change of different phases of the action potential is determined by the strict temporal organization of activation and inactivation of various ion channels. Transitions between functional states of the channel, including the transition to the slow inactivation state, can be influenced by a variety of factors and proteins interacting with the channel. Despite the fact that the process of slow inactivation of the channel has been known for several decades, its role in the mechanism of development of hereditary heart pathology remains unclear. In this work, using the method of local potential fixation (patch clamp) in a lead from a whole cell, we investigated changes in the process of slow inactivation of Na<sub>v</sub>1.5 under the influence of various mutations in structural genes (<i>DSP</i>-H1684R, <i>LMNA</i>-R249Q, <i>FLNC</i>-R1267Q, and <i>FLNC</i>-V2264M), associated with genetically determined myocardial pathology, leading to dysfunction of cardiomyocytes. We used a model of cardiomyocytes differentiated from induced pluripotent stem cells (CM-iPSCs) and demonstrated enhancement of slow channel inactivation in a model of CM-iPSCs obtained from patients with a cardiomyopathy phenotype combined with ventricular arrhythmias. Thus, the presented work contributes to understanding the role of the process of slow inactivation of Na<sub>v</sub>1.5 in the mechanism of development of heart pathology.</p>","PeriodicalId":9705,"journal":{"name":"Cell and Tissue Biology","volume":"44 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell and Tissue Biology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1134/s1990519x24700263","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"Biochemistry, Genetics and Molecular Biology","Score":null,"Total":0}
引用次数: 0
Abstract
Cardiac voltage-gated Nav1.5 sodium channels are responsible for initiation and propagation of action potentials in cardiomyocytes. Nav1.5 dysfunction may be due to both pathogenic variants in the gene itself SCN5A, encoding Nav1.5, and genetic variants in the genes of other proteins that regulate its activity and transport. The change of different phases of the action potential is determined by the strict temporal organization of activation and inactivation of various ion channels. Transitions between functional states of the channel, including the transition to the slow inactivation state, can be influenced by a variety of factors and proteins interacting with the channel. Despite the fact that the process of slow inactivation of the channel has been known for several decades, its role in the mechanism of development of hereditary heart pathology remains unclear. In this work, using the method of local potential fixation (patch clamp) in a lead from a whole cell, we investigated changes in the process of slow inactivation of Nav1.5 under the influence of various mutations in structural genes (DSP-H1684R, LMNA-R249Q, FLNC-R1267Q, and FLNC-V2264M), associated with genetically determined myocardial pathology, leading to dysfunction of cardiomyocytes. We used a model of cardiomyocytes differentiated from induced pluripotent stem cells (CM-iPSCs) and demonstrated enhancement of slow channel inactivation in a model of CM-iPSCs obtained from patients with a cardiomyopathy phenotype combined with ventricular arrhythmias. Thus, the presented work contributes to understanding the role of the process of slow inactivation of Nav1.5 in the mechanism of development of heart pathology.
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The journal publishes papers on vast aspects of cell research, including morphology, biochemistry, biophysics, genetics, molecular biology, immunology. The journal accepts original experimental studies, theoretical articles suggesting novel principles and approaches, presentations of new hypotheses, reviews highlighting major developments in cell biology, discussions. The main objective of the journal is to provide a competent representation and integration of research made on cells (animal and plant cells, both in vivo and in cell culture) offering insight into the structure and functions of live cells as a whole. Characteristically, the journal publishes articles on biology of free-living and parasitic protists, which, unlike Metazoa, are eukaryotic organisms at the cellular level of organization.
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