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Cx43 hemichannel microdomain signaling at the intercalated disc enhances cardiac excitability

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Abstract
Cx43, a major cardiac connexin, forms precursor hemichannels that accrue at the intercalated disc to assemble as gap junctions. While gap junctions are crucial for electrical conduction in the heart, little is known about the potential roles of hemichannels. Recent evidence suggests that inhibiting Cx43 hemichannel opening with Gap19 has antiarrhythmic effects. Here, we used multiple electrophysiology, imaging, and super-resolution techniques to understand and define the conditions underlying Cx43 hemichannel activation in ventricular cardiomyocytes, their contribution to diastolic Ca2+ release from the sarcoplasmic reticulum, and their impact on electrical stability. We showed that Cx43 hemichannels were activated during diastolic Ca2+ release in single ventricular cardiomyocytes and cardiomyocyte cell pairs from mice and pigs. This activation involved Cx43 hemichannel Ca2+ entry and coupling to Ca2+ release microdomains at the intercalated disc, resulting in enhanced Ca2+ dynamics. Hemichannel opening furthermore contributed to delayed afterdepolarizations and triggered action potentials. In single cardiomyocytes, cardiomyocyte cell pairs, and arterially perfused tissue wedges from failing human hearts, increased hemichannel activity contributed to electrical instability compared with nonfailing rejected donor hearts. We conclude that microdomain coupling between Cx43 hemichannels and Ca2+ release is a potentially novel, targetable mechanism of cardiac arrhythmogenesis in heart failure.
Keywords
Arrhythmias, Calcium signaling, Cardiology, Cell Biology, Peptides, CONDUCTANCE CATION CHANNEL, RYANODINE RECEPTORS, SARCOPLASMIC-RETICULUM, CA2+ RELEASE, CONNEXIN-43 IMPACTS, CALCIUM-RELEASE, NA/CA EXCHANGE, SODIUM CURRENT, MITOCHONDRIAL, MODULATION

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MLA
De Smet, Maarten, et al. “Cx43 Hemichannel Microdomain Signaling at the Intercalated Disc Enhances Cardiac Excitability.” JOURNAL OF CLINICAL INVESTIGATION, vol. 131, no. 7, 2021, doi:10.1172/jci137752.
APA
De Smet, M., Lissoni, A., Nezlobinskii, T., Wang, N., Dries, E., Pérez-Hernández, M., … Leybaert, L. (2021). Cx43 hemichannel microdomain signaling at the intercalated disc enhances cardiac excitability. JOURNAL OF CLINICAL INVESTIGATION, 131(7). https://doi.org/10.1172/jci137752
Chicago author-date
De Smet, Maarten, Alessio Lissoni, Timur Nezlobinskii, Nan Wang, Eef Dries, Marta Pérez-Hernández, Xianming Lin, et al. 2021. “Cx43 Hemichannel Microdomain Signaling at the Intercalated Disc Enhances Cardiac Excitability.” JOURNAL OF CLINICAL INVESTIGATION 131 (7). https://doi.org/10.1172/jci137752.
Chicago author-date (all authors)
De Smet, Maarten, Alessio Lissoni, Timur Nezlobinskii, Nan Wang, Eef Dries, Marta Pérez-Hernández, Xianming Lin, Matthew Amoni, Tim Vervliet, Katja Witschas, Eli Rothenberg, Geert Bultynck, Rainer Schulz, Alexander Panfilov, Mario Delmar, Karin R. Sipido, and Luc Leybaert. 2021. “Cx43 Hemichannel Microdomain Signaling at the Intercalated Disc Enhances Cardiac Excitability.” JOURNAL OF CLINICAL INVESTIGATION 131 (7). doi:10.1172/jci137752.
Vancouver
1.
De Smet M, Lissoni A, Nezlobinskii T, Wang N, Dries E, Pérez-Hernández M, et al. Cx43 hemichannel microdomain signaling at the intercalated disc enhances cardiac excitability. JOURNAL OF CLINICAL INVESTIGATION. 2021;131(7).
IEEE
[1]
M. De Smet et al., “Cx43 hemichannel microdomain signaling at the intercalated disc enhances cardiac excitability,” JOURNAL OF CLINICAL INVESTIGATION, vol. 131, no. 7, 2021.
@article{8695641,
  abstract     = {{Cx43, a major cardiac connexin, forms precursor hemichannels that accrue at the intercalated disc to assemble as gap junctions. While gap junctions are crucial for electrical conduction in the heart, little is known about the potential roles of hemichannels. Recent evidence suggests that inhibiting Cx43 hemichannel opening with Gap19 has antiarrhythmic effects. Here, we used multiple electrophysiology, imaging, and super-resolution techniques to understand and define the conditions underlying Cx43 hemichannel activation in ventricular cardiomyocytes, their contribution to diastolic Ca2+ release from the sarcoplasmic reticulum, and their impact on electrical stability. We showed that Cx43 hemichannels were activated during diastolic Ca2+ release in single ventricular cardiomyocytes and cardiomyocyte cell pairs from mice and pigs. This activation involved Cx43 hemichannel Ca2+ entry and coupling to Ca2+ release microdomains at the intercalated disc, resulting in enhanced Ca2+ dynamics. Hemichannel opening furthermore contributed to delayed afterdepolarizations and triggered action potentials. In single cardiomyocytes, cardiomyocyte cell pairs, and arterially perfused tissue wedges from failing human hearts, increased hemichannel activity contributed to electrical instability compared with nonfailing rejected donor hearts. We conclude that microdomain coupling between Cx43 hemichannels and Ca2+ release is a potentially novel, targetable mechanism of cardiac arrhythmogenesis in heart failure.}},
  articleno    = {{e137752}},
  author       = {{De Smet, Maarten and Lissoni, Alessio and Nezlobinskii, Timur and Wang, Nan and Dries, Eef and Pérez-Hernández, Marta and Lin, Xianming and Amoni, Matthew and Vervliet, Tim and Witschas, Katja and Rothenberg, Eli and Bultynck, Geert and Schulz, Rainer and Panfilov, Alexander and Delmar, Mario and Sipido, Karin R. and Leybaert, Luc}},
  issn         = {{0021-9738}},
  journal      = {{JOURNAL OF CLINICAL INVESTIGATION}},
  keywords     = {{Arrhythmias,Calcium signaling,Cardiology,Cell Biology,Peptides,CONDUCTANCE CATION CHANNEL,RYANODINE RECEPTORS,SARCOPLASMIC-RETICULUM,CA2+ RELEASE,CONNEXIN-43 IMPACTS,CALCIUM-RELEASE,NA/CA EXCHANGE,SODIUM CURRENT,MITOCHONDRIAL,MODULATION}},
  language     = {{eng}},
  number       = {{7}},
  pages        = {{20}},
  title        = {{Cx43 hemichannel microdomain signaling at the intercalated disc enhances cardiac excitability}},
  url          = {{http://dx.doi.org/10.1172/jci137752}},
  volume       = {{131}},
  year         = {{2021}},
}

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