Desmoglein-2 interaction is crucial for cardiomyocyte cohesion and function

Schlipp, Angela; Schinner, Camilla; Spindler, Volker; Vielmuth, Franziska; Gehmlich, Katja; Syrris, Petros; McKenna, William J.; Dendorfer, Andreas; Hartlieb, Eva; Waschke, Jens

doi:10.1093/cvr/cvu206

Cited by 62 publications

(78 citation statements)

References 28 publications

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“…Our strategy for preparing a rationally designed antagonist of β1-mediated adhesion was based on an approach successfully applied to two other adhesion proteins of the Ig domain family that share homologies with β1: N-cad (Williams et al, 2000a; Williams et al, 2000b) and desmoglein-1 (Schlipp et al, 2014). This method involves synthesizing a peptide mimicking the adhesion sequence within the Ig loop domain.…”

Section: Resultsmentioning

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

105

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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Section: Resultsmentioning

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

105

173

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“…10,12,29 In vitro experimentation further supports an adhesive function of Dsg2. Expression of different human AC-related Dsg2 mutants and inhibition of Dsg2 adhesion were reported to reduce adhesion upon expression in HL-1 cardiomyocytes 22 (for contrasting results on another mutant see Gaertner et al 30 ). The situation in other AC types is less clear.…”

Section: Discussionmentioning

confidence: 99%

“…19,20 The deleted part of Dsg2 includes the most aminoterminal calcium-binding site and is believed to be important for adhesion through homo-and heterophilic desmosomal cadherin interaction. 21 Thus, peptides taken from this domain prevent Dsg2-dependent adhesion, 22 and autoantibodies targeting the corresponding region in Dsg3 induce cell dissociation in pemphigus vulgaris. 23 Taken together, neither overexpression nor ≈50% reduction of WT Dsg2 induces overt cardiomyopathy.…”

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confidence: 99%

Desmoglein 2–Dependent Arrhythmogenic Cardiomyopathy Is Caused by a Loss of Adhesive Function

Kant

Holthöfer

Magin

et al. 2015

Circ Cardiovasc Genet

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Background— The desmosomal cadherin desmoglein 2 (Dsg2) localizes to the intercalated disc coupling adjacent cardiomyocytes. Desmoglein 2 gene ( DSG2 ) mutations cause arrhythmogenic cardiomyopathy (AC) in human and transgenic mice. AC is characterized by arrhythmia, cardiodilation, cardiomyocyte necrosis with replacement fibrosis, interstitial fibrosis, and intercalated disc dissociation. The genetic DSG2 constellations encountered are compatible with loss of adhesion and altered signaling. To further elucidate pathomechanisms, we examined whether heart-specific Dsg2 depletion triggers cardiomyopathy. Methods and Results— Because DSG2 knockouts die during early embryogenesis, mice were prepared with cardiomyocyte-specific DSG2 ablation. Healthy transgenic animals were born with a functional heart presenting intercalated discs with incorporated desmosomal proteins. Dsg2 protein expression was reduced below 3% in the heart. All animals developed AC during postnatal growth with pronounced chamber dilation, calcifying cardiomyocyte necrosis, aseptic inflammation, interstitial and focal replacement fibrosis, and conduction defects with altered connexin 43 distribution. Electron microscopy revealed absence of desmosome-like structures and regional loss of intercalated disc adhesion. Mice carrying 2 mutant DSG2 alleles coding for Dsg2 lacking part of the adhesive EC1-EC2 domains present an indistinguishable phenotype, which is similar to that observed in human AC patients. Conclusions— The observations show that the presence of Dsg2 is not essential for late heart morphogenesis and for cardiac contractility to support postnatal life. On increasing mechanical demands, heart function is severely compromised as evidenced by the onset of cardiomyopathy with pronounced morphological alterations. We propose that loss of Dsg2 compromises adhesion, and that this is a major pathogenic mechanism in DSG2 -related and probably other desmosome-related ACs.

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“…By coupling recombinant adhesion molecules to the tip of a flexible cantilever it is possible to simultaneously map the topography of a cell, the distribution of the ligand of that adhesion molecule and the adhesive forces of the bonds formed between the adhesion molecule and its binding partners on the cell surface (Carvalho and Santos, 2012;Hinterdorfer and Dufrene, 2006). Recently, we extended our previous cell-free binding studies of desmosomal cadherins (Gliem et al, 2010;Heupel et al, 2008;Schlipp et al, 2014;Spindler et al, 2009;Spindler et al, 2013;Waschke et al, 2007) to the measurement of Dsg3 adhesive properties on living keratinocytes (Vielmuth et al, 2014). This now enables us to map Dsg3 on living cells in presence of pemphigus autoantibodies and to simultaneously modulate signaling pathways to elucidate to contribution of direct inhibition and signaling mechanisms to loss of cell cohesion.…”

Section: Introductionmentioning

confidence: 97%

Loss of Desmoglein Binding Is Not Sufficient for Keratinocyte Dissociation in Pemphigus

Vielmuth

Waschke

Spindler

2015

Journal of Investigative Dermatology

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Pemphigus vulgaris (PV) is a severe autoimmune disease in which autoantibodies against the desmosomal cell adhesion molecules desmoglein (Dsg) 1 and Dsg3 cause intraepidermal blister formation. Mechanistically, the fundamental question is still unresolved whether loss of cell cohesion is a result of (1) direct inhibition of Dsg interaction by autoantibodies or (2) intracellular signaling events, which are altered in response to antibody binding and finally cause desmosome destabilization. We used atomic force microscopy (AFM) to perform Dsg3 adhesion measurements on living keratinocytes to investigate the contributions of direct inhibition and signaling to loss of cell cohesion after autoantibody treatment. Dsg3 binding was rapidly blocked following antibody exposure under conditions where no depletion of surface Dsg3 was detectable, demonstrating direct inhibition of Dsg3 interaction. Inhibition of p38MAPK, a central signaling molecule in PV pathogenesis, abrogated loss of cell cohesion, but had a minor effect on loss of Dsg3 binding. Similarly, the cholesterol-depleting agent methyl-β-cyclodextrin (β-MCD) fully blocked cell dissociation, but did not restore Dsg3 interactions or prevent the activation of p38MAPK. These results demonstrate that inhibition of Dsg3 binding is not sufficient to cause loss of cell cohesion, but rather alters signaling events which, in lipid raft-dependent manner, induce cell dissociation.

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Desmoglein-2 interaction is crucial for cardiomyocyte cohesion and function

Abstract: Our data demonstrate that desmoglein-2 plays a critical role in cardiomyocyte cohesion and function.

Cited by 62 publications

References 28 publications

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

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

Desmoglein 2–Dependent Arrhythmogenic Cardiomyopathy Is Caused by a Loss of Adhesive Function

Loss of Desmoglein Binding Is Not Sufficient for Keratinocyte Dissociation in Pemphigus

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