Details

Autor(en) / Beteiligte

• De Smet, Maarten A.J
• Lissoni, Alessio
• Nezlobinsky, Timur
• Wang, Nan
• Dries, Eef
• Perez-Hernandez, Marta
• Lin, Xianming
• Amoni, Matthew
• Vervliet, Tim
• Witschas, Katja
• Rothenberg, Eli
• Bultynck, Geert
• Schulz, Rainer
• Panfilov, Alexander V
• Delmar, Mario
• Sipido, Karin R
• Leybaert, Luc

Titel

Cx43 hemichannel microdomain signaling at the intercalated disc enhances cardiac excitability

Ist Teil von

• The Journal of clinical investigation, 2021-04, Vol.131 (7)

Ort / Verlag

American Society for Clinical Investigation

Erscheinungsjahr

2021

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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 [Ca.sup.2+] release from the sarcoplasmic reticulum, and their impact on electrical stability. We showed that Cx43 hemichannels were activated during diastolic [Ca.sup.2+] release in single ventricular cardiomyocytes and cardiomyocyte cell pairs from mice and pigs. This activation involved Cx43 hemichannel [Ca.sup.2+] entry and coupling to [Ca.sup.2+] release microdomains at the intercalated disc, resulting in enhanced [Ca.sup.2+] 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 [Ca.sup.2+] release is a potentially novel, targetable mechanism of cardiac arrhythmogenesis in heart failure.