Cx43 hemichannel microdomain signaling at the intercalated disc enhances cardiac excitability

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

doi:10.1172/jci137752

Cited by 61 publications

(75 citation statements)

References 62 publications

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“…In addition, some of the lateral connexins may not represent complete functional gap junctions but Cx43 hemichannels. These have been shown to be coupled to Ca 2+ release and Ca 2+ dynamics, so that in failing hearts hemichannel opening can contribute to delayed afterdepolarizations, triggered action potentials, and electrical instability (De Smet et al, 2021) [112]. Further investigations have demonstrated that the activation of ryanodine receptors (Ry2R) can open Cx43 hemichannels (Lissoni et al, 2021) [113].…”

Section: Gap Junction Remodeling In Cardiomyopathymentioning

confidence: 99%

Remodeling of Cardiac Gap Junctional Cell–Cell Coupling

Dhein

Salameh

2021

Cells

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The heart works as a functional syncytium, which is realized via cell-cell coupling maintained by gap junction channels. These channels connect two adjacent cells, so that action potentials can be transferred. Each cell contributes a hexameric hemichannel (=connexon), formed by protein subuntis named connexins. These hemichannels dock to each other and form the gap junction channel. This channel works as a low ohmic resistor also allowing the passage of small molecules up to 1000 Dalton. Connexins are a protein family comprising of 21 isoforms in humans. In the heart, the main isoforms are Cx43 (the 43 kDa connexin; ubiquitous), Cx40 (mostly in atrium and specific conduction system), and Cx45 (in early developmental states, in the conduction system, and between fibroblasts and cardiomyocytes). These gap junction channels are mainly located at the polar region of the cardiomyocytes and thus contribute to the anisotropic pattern of cardiac electrical conductivity. While in the beginning the cell–cell coupling was considered to be static, similar to an anatomically defined structure, we have learned in the past decades that gap junctions are also subject to cardiac remodeling processes in cardiac disease such as atrial fibrillation, myocardial infarction, or cardiomyopathy. The underlying remodeling processes include the modulation of connexin expression by e.g., angiotensin, endothelin, or catecholamines, as well as the modulation of the localization of the gap junctions e.g., by the direction and strength of local mechanical forces. A reduction in connexin expression can result in a reduced conduction velocity. The alteration of gap junction localization has been shown to result in altered pathways of conduction and altered anisotropy. In particular, it can produce or contribute to non-uniformity of anisotropy, and thereby can pre-form an arrhythmogenic substrate. Interestingly, these remodeling processes seem to be susceptible to certain pharmacological treatment.

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Section: Gap Junction Remodeling In Cardiomyopathymentioning

confidence: 99%

Remodeling of Cardiac Gap Junctional Cell–Cell Coupling

Dhein

Salameh

2021

Cells

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“…Bone remodelling processes Cx43 Mechanical stimulation [6][7][8] Cardiac ischemia/reperfusion injury Cx43 Phosphorylation of connexin proteins [9][10][11][12] Cataract Cx50 Oxidative stress [13] Charcot-Marie-Tooth disease Cx32…”

Section: Pathological Condition Connexin Species Mechanism Of Conneximentioning

confidence: 99%

“…Furthermore, relocated Cx43 may operate as open hemichannels. Preventing the loss of critic metabolites, restoring ionic imbalance, hindering cellular swelling and cell rupture via blocking these channels all are protective against myocardial ischemia/reperfusion injury [11,12]. However, it remains difficult to determine a general mechanism for the effects of phosphorylation on connexin hemichannel activity as there is a difference between the connexin family members.…”

Section: Phosphorylationmentioning

confidence: 99%

Mechanisms Underlying Connexin Hemichannel Activation in Disease

Campenhout

Gomes

Groof

et al. 2021

IJMS

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Gap junctions and connexin hemichannels mediate intercellular and extracellular communication, respectively. While gap junctions are seen as the “good guys” by controlling homeostasis, connexin hemichannels are considered as the “bad guys”, as their activation is associated with the onset and dissemination of disease. Open connexin hemichannels indeed mediate the transport of messengers between the cytosol and extracellular environment and, by doing so, fuel inflammation and cell death in a plethora of diseases. The present mini-review discusses the mechanisms involved in the activation of connexin hemichannels during pathology.

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“…In contrast with GJ, hemichannels are usually closed in basal conditions ( Contreras et al, 2003 ). However, metabolic inhibition, low extracellular or high intracellular calcium (Ca 2+ ) levels can trigger hemichannel opening, thereby allowing communication between the cytoplasm and the extracellular milieu ( Lissoni et al, 2021 ), which has been associated with arrhythmogenesis in heart failure (HF) ( De Smet et al, 2021 ). Although the human genome encodes for 21 different connexins, working cardiomyocytes and the cardiac conduction system mainly express Cx43, Cx40 and Cx45 ( Verheule and Kaese, 2013 ).…”

Section: Direct Cell–cell Communication Mechanismsmentioning

confidence: 99%

Connecting different heart diseases through intercellular communication

Martins‐Marques

2021

Biology Open

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Well-orchestrated intercellular communication networks are pivotal to maintaining cardiac homeostasis and to ensuring adaptative responses and repair after injury. Intracardiac communication is sustained by cell–cell crosstalk, directly via gap junctions (GJ) and tunneling nanotubes (TNT), indirectly through the exchange of soluble factors and extracellular vesicles (EV), and by cell–extracellular matrix (ECM) interactions. GJ-mediated communication between cardiomyocytes and with other cardiac cell types enables electrical impulse propagation, required to sustain synchronized heart beating. In addition, TNT-mediated organelle transfer has been associated with cardioprotection, whilst communication via EV plays diverse pathophysiological roles, being implicated in angiogenesis, inflammation and fibrosis. Connecting various cell populations, the ECM plays important functions not only in maintaining the heart structure, but also acting as a signal transducer for intercellular crosstalk. Although with distinct etiologies and clinical manifestations, intercellular communication derailment has been implicated in several cardiac disorders, including myocardial infarction and hypertrophy, highlighting the importance of a comprehensive and integrated view of complex cell communication networks. In this review, I intend to provide a critical perspective about the main mechanisms contributing to regulate cellular crosstalk in the heart, which may be considered in the development of future therapeutic strategies, using cell-based therapies as a paradigmatic example. This Review has an associated Future Leader to Watch interview with the author.

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Cx43 hemichannel microdomain signaling at the intercalated disc enhances cardiac excitability

Cited by 61 publications

References 62 publications

Remodeling of Cardiac Gap Junctional Cell–Cell Coupling

Remodeling of Cardiac Gap Junctional Cell–Cell Coupling

Mechanisms Underlying Connexin Hemichannel Activation in Disease

Connecting different heart diseases through intercellular communication

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