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.
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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

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Figure 2

Cx43 HC activation in ventricular cardiomyocytes.

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Cx43 HC activation in ventricular cardiomyocytes. (A–C) Cx43 HC states a...
(A–C) Cx43 HC states and the effect of Gap19 and CT9 peptides. (A) Interaction of the CT tail with the CL brings HCs into the “available to open” state. (B) Gap19 interaction with the CT prevents CT-CL interaction, making HCs unavailable for opening. (C) CT9 peptide interaction with the CL brings HCs into the “available to open” state. (D) Bell-shaped [Ca2+]i dependency of HC opening. CT9 removes HC inhibition at above 500 nM [Ca2+]i (dashed line), thereby strongly enhancing HC opening. (E) Caffeine activation of RyRs triggers [Ca2+]i elevation (brown trace) followed by NCX current (black) associated with Ca2+ extrusion. Spiking HC opening activity appears superimposed on the NCX current. At the start of caffeine application, simultaneous (stacked spikes) HC openings can be distinguished resulting from up to three HCs. (F) HC opening in ventricular cardiomyocytes requires three conditions: (a) activation of RyR2 by caffeine, adrenergic stress, or rapid electrical pacing; (b) [Ca2+]i elevation; and (c) molecular interaction between RyR2 and Cx43 HCs (inhibited by RyRHCIp peptide). (G) Open HCs carry inward current producing about 1.6 mV depolarization per HC (at –70 mV diastolic potential). HC Ca2+ entry triggers microdomain Ca2+ elevation that is extruded by NCX activity, adding another 1.3 mV depolarization, yielding almost 3 mV depolarization per HC. HC opening events are brief (~8 milliseconds on average) but sufficiently long to obtain steady-state membrane charge redistribution and achieve the approximately 3 mV depolarization estimate.