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|Cx43 hemichannel microdomain signaling at the intercalated disc enhances cardiac excitability
|de, Smet, M. A. J.
Panfilov, A. V.
Sipido, K. R.
|American Society for Clinical Investigation
|Cx43 hemichannel microdomain signaling at the intercalated disc enhances cardiac excitability / M. A. J. de Smet, A. Lissoni, T. Nezlobinsky, et al. — DOI 10.1172/JCI137752 // Journal of Clinical Investigation. — 2021. — Vol. 131. — Iss. 7. — e137752.
|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. Copyright: © 2021, American Society for Clinical Investigation.
RYANODINE RECEPTOR 2
BETA ADRENERGIC STIMULATION
CARDIAC MUSCLE CELL
HEART MUSCLE EXCITABILITY
HEART MUSCLE POTENTIAL
MEMBRANE STEADY POTENTIAL
|We sincerely thank Ellen Cocquyt, Diego De Baere, Vicky Pauwelyn, Annemie Biesemans, Roxane Menten, and Mingliang Zhang for superb technical support. We would also like to thank the heart failure unit, the transplant surgical team, and the transplant coordinating team of UZ Leuven for help in providing the human explant hearts. This work was supported by the Fund for Scientific Research Flanders (project grants to LL, KRS, and GB; a postdoctoral fellowship to ED; and PhD fellowships to MDS and MA); Ghent University (a postdoctoral fellowship to KW and PhD fellowships to AL and TN); the Interuniversity Attraction Poles P7/10 to KRS and LL; NIH (project grants to ER and MD); the Fondation Leducq (transatlantic network award to MD); and a grant from the Ministry of Science and Higher Education of the Russian Federation, agreement 075-15-2020-800, to AVP.
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