Connexin-43 (Cx43) is the most abundant protein forming gap junction channels (GJCs) in cardiac ventricles. In multiple cardiac pathologies, including hypertrophy and heart failure, Cx43 is found remodeled at the lateral side of the intercalated discs of ventricular cardiomyocytes. Remodeling of Cx43 has been long linked to spontaneous ventricular arrhythmia, yet the mechanisms by which arrhythmias develop are still debated. Using a model of dystrophic cardiomyopathy, we previously showed that remodeled Cx43 function as aberrant hemichannels (non-forming GJCs) that alter cardiomyocyte excitability and, consequently, promote arrhythmias. Here, we aim to evaluate if opening of remodeled Cx43 can serve as a general mechanism to alter cardiac excitability independent of cellular dysfunction associated with a particular cardiomyopathy. To address this issue, we used a genetically modified Cx43 knock-in mouse (S3A) that promotes cardiac remodeling of Cx43 protein without apparent cardiac dysfunction. Importantly, when S3A mice were subjected to cardiac stress using the β-adrenergic agonist isoproterenol (Iso), they displayed acute and severe arrhythmias, which were not observed in WT mice. Pretreatment of S3A mice with the Cx43 hemichannel blocker, Gap19, prevented Iso-induced abnormal electrocardiographic behavior. At the cellular level, when compared with WT, Iso-treated S3A cardiomyocytes showed increased membrane permeability, greater plasma membrane depolarization, and Ca2+ overload, which likely caused prolonged action potentials, delayed after depolarizations, and triggered activity. All these cellular dysfunctions were also prevented by Cx43 hemichannel blockers. Our results support the notion that opening of remodeled Cx43 hemichannels, regardless of the type of cardiomyopathy, is sufficient to mediate cardiac-stress-induced arrhythmogenicity.
Skip Nav Destination
Article navigation
3 July 2023
Article|
May 16 2023
Remodeled connexin 43 hemichannels alter cardiac excitability and promote arrhythmias
Mauricio A. Lillo
,
Mauricio A. Lillo
(Conceptualization, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing)
1Department of Pharmacology,
Physiology and Neuroscience, Rutgers University, New Jersey Medical School
, Newark, NJ, USA
Search for other works by this author on:
Manuel Muñoz
,
Manuel Muñoz
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing - original draft, Writing - review & editing)
2Department of Physiology and Membrane Biology,
University of California, Davis
. Davis, CA, USA
Search for other works by this author on:
Paula Rhana
,
Paula Rhana
(Formal analysis, Investigation, Methodology, Visualization, Writing - review & editing)
2Department of Physiology and Membrane Biology,
University of California, Davis
. Davis, CA, USA
Search for other works by this author on:
Kelli Gaul-Muller
,
Kelli Gaul-Muller
(Investigation, Writing - review & editing)
1Department of Pharmacology,
Physiology and Neuroscience, Rutgers University, New Jersey Medical School
, Newark, NJ, USA
Search for other works by this author on:
Jonathan Quan
,
Jonathan Quan
(Investigation, Writing - review & editing)
2Department of Physiology and Membrane Biology,
University of California, Davis
. Davis, CA, USA
Search for other works by this author on:
Natalia Shirokova
,
Natalia Shirokova
(Conceptualization, Funding acquisition, Software, Supervision)
1Department of Pharmacology,
Physiology and Neuroscience, Rutgers University, New Jersey Medical School
, Newark, NJ, USA
Search for other works by this author on:
Lai-Hua Xie
,
Lai-Hua Xie
(Formal analysis, Methodology, Resources, Supervision, Writing - review & editing)
3Department of Cell Biology and Molecular Medicine,
Rutgers University, New Jersey Medical School
, Newark, NJ, USA
Search for other works by this author on:
Luis Fernando Santana
,
Luis Fernando Santana
(Data curation, Formal analysis, Methodology, Supervision, Writing - original draft, Writing - review & editing)
2Department of Physiology and Membrane Biology,
University of California, Davis
. Davis, CA, USA
Search for other works by this author on:
Diego Fraidenraich
,
Diego Fraidenraich
(Funding acquisition, Resources, Writing - review & editing)
3Department of Cell Biology and Molecular Medicine,
Rutgers University, New Jersey Medical School
, Newark, NJ, USA
Search for other works by this author on:
Jorge E. Contreras
(Conceptualization, Formal analysis, Funding acquisition, Methodology, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing)
1Department of Pharmacology,
Physiology and Neuroscience, Rutgers University, New Jersey Medical School
, Newark, NJ, USA
2Department of Physiology and Membrane Biology,
University of California, Davis
. Davis, CA, USA
Correspondence to Jorge E. Contreras: jecontrer@ucdavis.edu
Search for other works by this author on:
Mauricio A. Lillo
Conceptualization, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing
1Department of Pharmacology,
Physiology and Neuroscience, Rutgers University, New Jersey Medical School
, Newark, NJ, USA
Manuel Muñoz
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing - original draft, Writing - review & editing
2Department of Physiology and Membrane Biology,
University of California, Davis
. Davis, CA, USA
Paula Rhana
Formal analysis, Investigation, Methodology, Visualization, Writing - review & editing
2Department of Physiology and Membrane Biology,
University of California, Davis
. Davis, CA, USA
Kelli Gaul-Muller
Investigation, Writing - review & editing
1Department of Pharmacology,
Physiology and Neuroscience, Rutgers University, New Jersey Medical School
, Newark, NJ, USA
Jonathan Quan
Investigation, Writing - review & editing
2Department of Physiology and Membrane Biology,
University of California, Davis
. Davis, CA, USA
Natalia Shirokova
Conceptualization, Funding acquisition, Software, Supervision
1Department of Pharmacology,
Physiology and Neuroscience, Rutgers University, New Jersey Medical School
, Newark, NJ, USA
Lai-Hua Xie
Formal analysis, Methodology, Resources, Supervision, Writing - review & editing
3Department of Cell Biology and Molecular Medicine,
Rutgers University, New Jersey Medical School
, Newark, NJ, USA
Luis Fernando Santana
Data curation, Formal analysis, Methodology, Supervision, Writing - original draft, Writing - review & editing
2Department of Physiology and Membrane Biology,
University of California, Davis
. Davis, CA, USA
Diego Fraidenraich
Funding acquisition, Resources, Writing - review & editing
3Department of Cell Biology and Molecular Medicine,
Rutgers University, New Jersey Medical School
, Newark, NJ, USA
Jorge E. Contreras
Conceptualization, Formal analysis, Funding acquisition, Methodology, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1Department of Pharmacology,
Physiology and Neuroscience, Rutgers University, New Jersey Medical School
, Newark, NJ, USA
2Department of Physiology and Membrane Biology,
University of California, Davis
. Davis, CA, USA
Correspondence to Jorge E. Contreras: jecontrer@ucdavis.edu
Disclosures: The authors declare no competing interests exist.
Received:
March 21 2022
Revision Received:
January 25 2023
Revision Received:
April 06 2023
Accepted:
April 24 2023
Online ISSN: 1540-7748
Print ISSN: 0022-1295
Funding
Funder(s):
American Heart Association
- Award Id(s): 18POST339610107,932684,23POST1027462,16GRNT31100022
Funder(s):
National Institutes of Health
- Award Id(s): R01HL92929,R01Hl133294,1R01HL141170-01,1R01GM099490
Funder(s):
Muscular Dystrophy Association
- Award Id(s): 416281
© 2023 Lillo et al.
2023
Lillo et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Gen Physiol (2023) 155 (7): e202213150.
Article history
Received:
March 21 2022
Revision Received:
January 25 2023
Revision Received:
April 06 2023
Accepted:
April 24 2023
Citation
Mauricio A. Lillo, Manuel Muñoz, Paula Rhana, Kelli Gaul-Muller, Jonathan Quan, Natalia Shirokova, Lai-Hua Xie, Luis Fernando Santana, Diego Fraidenraich, Jorge E. Contreras; Remodeled connexin 43 hemichannels alter cardiac excitability and promote arrhythmias. J Gen Physiol 3 July 2023; 155 (7): e202213150. doi: https://doi.org/10.1085/jgp.202213150
Download citation file:
Sign in
Don't already have an account? Register
Client Account
You could not be signed in. Please check your email address / username and password and try again.
Captcha Validation Error. Please try again.
Sign in via your Institution
Sign in via your InstitutionSuggested Content
Email alerts
Advertisement