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

Figures

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  Figure 1. Connexins in the heart and Cx43 topology with indication of crucial sites and interactions that are discussed in this Review. 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,…

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  Figure 2. Cx43 HC activation in ventricular cardiomyocytes. (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…

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  Figure 3. Contribution of Cx43 HCs to ventricular and atrial arrhythmogenesis. Overview of signaling cascades leading to HC-related arrhythmic responses in ventricular (A–D) and atrial cardiomyocytes (E). Arrhythmogenic consequences of HC opening are given for the ventricular cascades A–E and are further explained in the main text. APD, action potential duration; cKO, conditional knockout; CM, cardiomyocyte; NAD+, nicotinamide adenine dinucleotide; ventr., ventricular.