Connexin hemichannels as candidate targets for cardioprotective and anti-arrhythmic treatments
Luc Leybaert, … , Karin R. Sipido, Katja Witschas
Luc Leybaert, … , Karin R. Sipido, Katja Witschas
Published March 15, 2023
Citation Information: J Clin Invest. 2023;133(6):e168117. https://doi.org/10.1172/JCI168117.
View: Text | PDF
Review

Connexin hemichannels as candidate targets for cardioprotective and anti-arrhythmic treatments

Abstract

Connexins are crucial cardiac proteins that form hemichannels and gap junctions. Gap junctions are responsible for the propagation of electrical and chemical signals between myocardial cells and cells of the specialized conduction system in order to synchronize the cardiac cycle and steer cardiac pump function. Gap junctions are normally open, while hemichannels are closed, but pathological circumstances may close gap junctions and open hemichannels, thereby perturbing cardiac function and homeostasis. Current evidence demonstrates an emerging role of hemichannels in myocardial ischemia and arrhythmia, and tools are now available to selectively inhibit hemichannels without inhibiting gap junctions as well as to stimulate hemichannel incorporation into gap junctions. We review available experimental evidence for hemichannel contributions to cellular pro-arrhythmic events in ventricular and atrial cardiomyocytes, and link these to insights at the level of molecular control of connexin-43–based hemichannel opening. We conclude that a double-edged approach of both preventing hemichannel opening and preserving gap junctional function will be key for further research and development of new connexin-based experimental approaches for treating heart disease.

Authors

Luc Leybaert, Maarten A.J. De Smet, Alessio Lissoni, Rosalie Allewaert, H. Llewelyn Roderick, Geert Bultynck, Mario Delmar, Karin R. Sipido, Katja Witschas

×

Figure 1

Connexins in the heart and Cx43 topology with indication of crucial sites and interactions that are discussed in this Review.

Options: View larger image (or click on image) Download as PowerPoint
Connexins in the heart and Cx43 topology with indication of crucial site...
The upper right image illustrates expression of Cx40, Cx43, and Cx45 in heart muscle, conduction tissues, and nodes. Cx43 is present in most of the tissues, except for the sinoatrial and atrioventricular nodes. Cx40 prevails in atrial cardiomyocytes and in the His-Purkinje system (23, 25, 152, 153), while Cx45 is primarily expressed in the conduction system (23). The Cx43 topology scheme indicates various regions and sequences that are discussed in this Review. Gap19, L2, Gap26, Gap27, and CT9 are sequences that have been used as mimetic peptides affecting Cx43 channel function as well as Cx43 interaction within or outside the protein. The sequences marked “Tubulin” and “RyR2” (ryanodine receptor-2) indicate interaction sites with these respective proteins. “CaM” indicates a calmodulin interaction site. “SH3” denotes an Src homology binding domain. H1 (315 to 326) and H2 (340 to 348) are α-helical structures. Ser325, Ser328, Ser330, and Ser368 are phosphorylation sites, while Cys271 is a nitrosylation site, which are discussed in the main text. NT, N-terminal end; CT, C-terminal end; EL1 and EL2, extracellular loops 1 and 2; CL, cytoplasmic loop; ZO-1, zonula occludens 1.