Gap junctions–guards of excitability

Stroemlund, Line Waring; Jensen, Christa Funch; Qvortrup, Klaus; Delmar, Mario; Nielsen, Morten Schak

doi:10.1042/bst20150059

Cited by 19 publications

(15 citation statements)

References 25 publications

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“…This is especially important in the heart, where the fine-tuned connexindependent cell-cell communication through gap junctions has been shown to be essential to ensure a coordinated contraction and pumping activity (see for instance Beyer et al, 1987;Revel and Karnovsky, 1967;Yeager and Gilula, 1992). Therefore, an impairment in GJIC has been implicated in the development of electric conduction defects that underlie several cardiac disorders (Severs, 2009;Severs et al, 2004;Stroemlund et al, 2015).…”

Section: The Role Of Gjic In the Heartmentioning

confidence: 99%

“…Interestingly, Cx43 expression has been suggested to be necessary for the full activity of Na + currents and for the accumulation of Na v 1.5 at the cardiac intercalated disc (Jansen et al, 2012;Lübkemeier et al, 2013). The disturbance of electrical coupling, which has been implicated in various cardiac disorders, including heart failure and arrhythmogenesis, appears to be modulated, at least in part, by Cx43 expression and distribution, as well as the gating properties of the Cx43 channels (Duffy, 2012;Severs et al, 2004;Stroemlund et al, 2015). For instance, defects of electrical conductance in cardiac ischaemia, which is associated with an increase in cytosolic Ca 2+ concentration, a decrease of intracellular pH and changes in the activity of different protein kinases and phosphatases, have been ascribed to the closure and internalization of gap junction channels, the appearance of Cx43 at the lateral membrane of cardiomyocytes ('lateralization') and the opening of non-opposed Cx43 hemichannels (Fig.…”

Section: The Role Of Gjic In the Heartmentioning

confidence: 99%

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Role of connexin 43 in different forms of intercellular communication – gap junctions, extracellular vesicles and tunnelling nanotubes

Ribeiro-Rodrigues

Martins‐Marques

Morel

et al. 2017

Journal of Cell Science

147

159

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Communication is important to ensure the correct and efficient flow of information, which is required to sustain active social networks. A fine-tuned communication between cells is vital to maintain the homeostasis and function of multicellular or unicellular organisms in a community environment. Although there are different levels of complexity, intercellular communication, in prokaryotes to mammalians, can occur through secreted molecules (either soluble or encapsulated in vesicles), tubular structures connecting close cells or intercellular channels that link the cytoplasm of adjacent cells. In mammals, these different types of communication serve different purposes, may involve distinct factors and are mediated by extracellular vesicles, tunnelling nanotubes or gap junctions. Recent studies have shown that connexin 43 (Cx43, also known as GJA1), a transmembrane protein initially described as a gap junction protein, participates in all these forms of communication; this emphasizes the concept of adopting strategies to maximize the potential of available resources by reutilizing the same factor in different scenarios. In this Review, we provide an overview of the most recent advances regarding the role of Cx43 in intercellular communication mediated by extracellular vesicles, tunnelling nanotubes and gap junctions.

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Section: The Role Of Gjic In the Heartmentioning

confidence: 99%

Section: The Role Of Gjic In the Heartmentioning

confidence: 99%

Role of connexin 43 in different forms of intercellular communication – gap junctions, extracellular vesicles and tunnelling nanotubes

Ribeiro-Rodrigues

Martins‐Marques

Morel

et al. 2017

Journal of Cell Science

147

159

View full text Add to dashboard Cite

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“…Moreover, as GJ remodeling occurs in multiple cardiac pathologies (Jongsma and Wilders, 2000; Stroemlund et al, 2015), it is widely held that disrupted GJ coupling is mechanistically central to arrhythmogenesis in heart disease (De Vuyst et al, 2011; Palatinus et al, 2012). Whilst a GJ-based paradigm for cardiac electrical coupling has been in place for over 50 years, a small group of mathematical biologists has proposed that cardiac conduction in health and disease may involve ephaptic mechanisms (Lin and Keener, 2010; Mann and Sperelakis, 1979; Mori et al, 2008; Pertsov and Medvinskiĭ, 1979).…”

Section: Introductionmentioning

confidence: 99%

The adhesion function of the sodium channel beta subunit (β1) contributes to cardiac action potential propagation

Veeraraghavan

Hoeker

Alvarez-Laviada

et al. 2018

eLife

102

173

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Computational modeling indicates that cardiac conduction may involve ephaptic coupling – intercellular communication involving electrochemical signaling across narrow extracellular clefts between cardiomyocytes. We hypothesized that β1(SCN1B) –mediated adhesion scaffolds trans-activating NaV1.5 (SCN5A) channels within narrow (<30 nm) perinexal clefts adjacent to gap junctions (GJs), facilitating ephaptic coupling. Super-resolution imaging indicated preferential β1 localization at the perinexus, where it co-locates with NaV1.5. Smart patch clamp (SPC) indicated greater sodium current density (INa) at perinexi, relative to non-junctional sites. A novel, rationally designed peptide, βadp1, potently and selectively inhibited β1-mediated adhesion, in electric cell-substrate impedance sensing studies. βadp1 significantly widened perinexi in guinea pig ventricles, and selectively reduced perinexal INa, but not whole cell INa, in myocyte monolayers. In optical mapping studies, βadp1 precipitated arrhythmogenic conduction slowing. In summary, β1-mediated adhesion at the perinexus facilitates action potential propagation between cardiomyocytes, and may represent a novel target for anti-arrhythmic therapies.

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“…In addition to cadherins, other receptors are targeted to the intercalated discs and regulate cardiomyocytes’ coupling. Specifically, connexin proteins are key components of gap junctions, structures specialized in intercellular electric coupling [6]. In the past years it has become clear that intercalated discs are dynamic structures that are a target of complex signaling events that can alter their composition and compromise their function during disease states.…”

Section: Introductionmentioning

confidence: 99%

TGF-β1 affects cell-cell adhesion in the heart in an NCAM1-dependent mechanism

Ackermann¹,

Petrosino²,

Manring³

et al. 2017

Journal of Molecular and Cellular Cardiology

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The contractile property of the myocardium is maintained by cell-cell junctions enabling cardiomyocytes to work as a syncytium. Alterations in cell-cell junctions are observed in heart failure, a disease characterized by the activation of Transforming Growth Factor beta 1 (TGFβ1). While TGFβ1 has been implicated in diverse biologic responses, its molecular function in controlling cell-cell adhesion in the heart has never been investigated. Cardiac-specific transgenic mice expressing active TGFβ1 were generated to model the observed increase in activity in the failing heart. Activation of TGFβ1 in the heart was sufficient to drive ventricular dysfunction. To begin to understand the function of this important molecule we undertook an extensive structural analysis of the myocardium by electron microscopy and immunostaining. This approach revealed that TGFβ1 alters intercalated disc structures and cell-cell adhesion in ventricular myocytes. Mechanistically, we found that TGFβ1 induces the expression of neural adhesion molecule 1 (NCAM1) in cardiomyocytes in a p38-dependent pathway, and that selective targeting of NCAM1 was sufficient to rescue the cell adhesion defect observed when cardiomyocytes were treated with TGFβ1. Importantly, NCAM1 was upregulated in human heart samples from ischemic and non-ischemic cardiomyopathy patients and NCAM1 protein levels correlated with the degree of TGFβ1 activity in the human cardiac ventricle. Overall, we found that TGFβ1 is deleterious to the heart by regulating the adhesion properties of cardiomyocytes in an NCAM1-dependent mechanism. Our results suggest that inhibiting NCAM1 would be cardioprotective, counteract the pathological action of TGFβ1 and reduce heart failure severity.

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Gap junctions–guards of excitability

Cited by 19 publications

References 25 publications

Role of connexin 43 in different forms of intercellular communication – gap junctions, extracellular vesicles and tunnelling nanotubes

Role of connexin 43 in different forms of intercellular communication – gap junctions, extracellular vesicles and tunnelling nanotubes

The adhesion function of the sodium channel beta subunit (β1) contributes to cardiac action potential propagation

TGF-β1 affects cell-cell adhesion in the heart in an NCAM1-dependent mechanism

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