Impact of the DSP-H1684R Genetic Variant on Ion Channels Activity in iPSC-Derived Cardiomyocytes.
Action Potentials
/ physiology
Calcium Channels
/ physiology
Cardiac Conduction System Disease
/ genetics
Desmoplakins
/ genetics
Fluorescent Antibody Technique
Heart Block
/ genetics
Humans
Induced Pluripotent Stem Cells
/ drug effects
Ion Channels
/ metabolism
Myocytes, Cardiac
/ metabolism
Patch-Clamp Techniques
Potassium Channels, Voltage-Gated
/ physiology
Voltage-Gated Sodium Channels
/ physiology
Arrhythmias; Cardiomyocytes; Desmoplakin; Induced pluripotent stem cells; Ion channels; Progressive cardiac conduction disease
Journal
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
ISSN: 1421-9778
Titre abrégé: Cell Physiol Biochem
Pays: Germany
ID NLM: 9113221
Informations de publication
Date de publication:
25 Jul 2020
25 Jul 2020
Historique:
accepted:
16
07
2020
entrez:
25
7
2020
pubmed:
25
7
2020
medline:
13
1
2021
Statut:
ppublish
Résumé
Mutations of desmosomal genes are known to cause arrhythmogenic cardiomyopathy characterized by arrhythmias and sudden cardiac death. Previously, we described a novel genetic variant H1684R in desmoplakin gene (DSP), associated with a progressive cardiac conduction disease (PCCD). In the present study, we aimed to investigate an effect of the DSP-H1684R genetic variant on the activity of ion channels. We used cardiomyocytes derived from induced pluripotent stem cells (iPSC cardiomyocytes) from a patient with DSP-H1684R genetic variant and from two healthy donors. Immunofluorescent staining and western blot analyses were used to characterize patient-specific cardiomyocytes. By the whole-cell voltage-clamp technique we estimated the activity of voltage-gated sodium, calcium, and potassium channels that are responsible for action potential generation and its shape. Action potentials' parameters were measured using whole-cell current-clamp technique. In patient-specific cardiomyocytes we observed both lower amplitudes of currents through sodium Na Our results show that desmoplakin genetic variants, besides conduction slowing caused by structural heart remodeling, could affect multiple ion channel activity aggravating arrhythmia manifestation in PCCD.
Sections du résumé
BACKGROUND/AIMS
OBJECTIVE
Mutations of desmosomal genes are known to cause arrhythmogenic cardiomyopathy characterized by arrhythmias and sudden cardiac death. Previously, we described a novel genetic variant H1684R in desmoplakin gene (DSP), associated with a progressive cardiac conduction disease (PCCD). In the present study, we aimed to investigate an effect of the DSP-H1684R genetic variant on the activity of ion channels.
METHODS
METHODS
We used cardiomyocytes derived from induced pluripotent stem cells (iPSC cardiomyocytes) from a patient with DSP-H1684R genetic variant and from two healthy donors. Immunofluorescent staining and western blot analyses were used to characterize patient-specific cardiomyocytes. By the whole-cell voltage-clamp technique we estimated the activity of voltage-gated sodium, calcium, and potassium channels that are responsible for action potential generation and its shape. Action potentials' parameters were measured using whole-cell current-clamp technique.
RESULTS
RESULTS
In patient-specific cardiomyocytes we observed both lower amplitudes of currents through sodium Na
CONCLUSION
CONCLUSIONS
Our results show that desmoplakin genetic variants, besides conduction slowing caused by structural heart remodeling, could affect multiple ion channel activity aggravating arrhythmia manifestation in PCCD.
Substances chimiques
Calcium Channels
0
Desmoplakins
0
Ion Channels
0
Potassium Channels, Voltage-Gated
0
Voltage-Gated Sodium Channels
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
696-706Subventions
Organisme : Russian Science Foundation
ID : 19-75-00070, 19-14-00114
Pays : Russia
Organisme : Russian Foundation for Basic Research
ID : 17-54-80006
Pays : Russia
Informations de copyright
© Copyright by the Author(s). Published by Cell Physiol Biochem Press.
Déclaration de conflit d'intérêts
The authors declare no competing interests.