Adrenergic Signaling Strengthens Cardiac Myocyte Cohesion

Schinner, Camilla; Vielmuth, Franziska; Rötzer, Vera; Hiermaier, Matthias; Radeva, Mariya Y.; Co, Thu Kim; Hartlieb, Eva; Schmidt, Andreas; Imhof, Axel; Messoudi, Ahmed; Horn, Anja K. E.; Schlipp, Angela; Spindler, Volker; Waschke, Jens

doi:10.1161/circresaha.116.309631

Cited by 56 publications

(162 citation statements)

References 49 publications

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“…Under baseline conditions, both proteins were distributed in a dot‐like fashion concentrated at the cell‐cell junctions (Figure D). Fitting to previous results, adrenergic signalling induced an increase and linearization of the signals for both proteins at the cell contact area, whereas Trp leads to formation of irregular DSG2 and DP signals mainly in the area of cell‐cell junctions as described previously . Combination of Trp with F/R treatment induced an accumulation of the investigated proteins similar to experiments using F/R alone.…”

Section: Resultssupporting

confidence: 84%

“…The degree of fractionation of the monolayer is inversely correlated with cell‐cell adhesion. As described previously, adrenergic stimulation via Iso or F/R treatment strengthened cardiac cell cohesion as indicated by reduced monolayer fragmentation (Figure A) and an excess of Trp was efficient to significantly reduce intercellular adhesion . Interestingly, F/R‐mediated increase in cAMP was sufficient to block the effect of Trp.…”

Section: Resultssupporting

confidence: 69%

“…As a tool to disrupt cadherin adhesion in general, an excess of Trp was applied to inhibit cadherin binding by blocking the swap of Trp residues at the tip of extracellular 1 domains . To compare the results with the effects of adrenergic signalling, we used either the β 1 ‐adrenergic receptor agonist isoprenaline (Iso) for direct receptor stimulation or a combination of the adenylyl cyclase activator forskolin and the phosphodiesterase‐4 inhibitor rolipram (F/R) to increase levels of the adrenergic second messenger cAMP …”

Section: Resultsmentioning

confidence: 99%

“…Thus, we hypothesized that not only gap junctions are regulated by desmosomal adhesion but also the β 1 ‐adrenergic receptor. To verify this, cadherin binding was impaired by Trp application or desmosomal adhesion was disrupted by depletion of the desmosomal adhesion molecule DSG2 or the plaque protein PG by specific siRNA (siDSG2, siPG) . Functionality of the β 1 ‐adrenergic receptor was determined by measurements of the levels of the second messenger cAMP in response to activation of the receptor by Iso.…”

Section: Resultsmentioning

confidence: 99%

“…Here, adrenergic stimulation—a major regulator of cardiac function—induces a shift of DSG2 together with PG and DP towards the cell junction paralleled with an increase of cell‐cell cohesion. This effect was dependent on PG and its phosphorylation at S665 by PKA …”

Section: Introductionmentioning

confidence: 96%

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Regulation of cardiac myocyte cohesion and gap junctions via desmosomal adhesion

et al. 2019

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Aims Mutations in desmosomal proteins can induce arrhythmogenic cardiomyopathy with life‐threatening arrhythmia. Previous data demonstrated adrenergic signalling to be important to regulate desmosomal cohesion in cardiac myocytes. Here, we investigated how signalling pathways including adrenergic signalling, PKC and SERCA regulate desmosomal adhesion and how this controls gap junctions (GJs) in cardiac myocytes. Methods Immunostaining, Western blot, dissociation assay and multi‐electrode array were applied in HL‐1 cardiac myocytes to evaluate localization, expression and function of desmosomal and GJ components. cAMP levels were determined by ELISA. Results Activation of PKC by PMA or adrenergic signalling increased cell cohesion and desmoglein‐2 and desmoplakin localization at cell‐cell junctions, whereas tryptophan (Trp) treatment to inhibit cadherin binding or inhibition of SERCA by thapsigargin reduced cell cohesion, while cAMP elevation rescued this effect. Despite no changes in protein expression, accumulation of GJ protein connexin‐43 was detectable at cell‐cell contacts in parallel to increased cohesion. Disruption of cell cohesion by Trp, PMA or thapsigargin impaired conduction of excitation comparable to GJ inhibition. cAMP elevation was effective to improve arrhythmia after Trp treatment. Weakened cell cohesion by Trp or depletion of desmoglein‐2 or plakoglobin blocked signalling via the β1‐adrenergic receptor. Moreover, silencing of desmosomal proteins increased arrhythmia and reduced conduction velocity, which were rescued by cAMP elevation. Conclusion These data demonstrate the interplay of GJs, desmosomes and the β1‐adrenergic receptor with regulation of their function by cell cohesion, adrenergic and PKC signalling or SERCA inhibition. These results support the identification of new targets to treat arrhythmogenic cardiomyopathy.

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Section: Resultssupporting

confidence: 84%

Section: Resultssupporting

confidence: 69%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

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Regulation of cardiac myocyte cohesion and gap junctions via desmosomal adhesion

et al. 2019

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Serine/threonine‐protein kinase D2‐mediated phosphorylation of DSG2 threonine 730 promotes esophageal squamous cell carcinoma progression

Liu,

Xu,

Zheng

et al. 2024

The Journal of Pathology

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Desmoglein‐2 (DSG2) is a transmembrane glycoprotein belonging to the desmosomal cadherin family, which mediates cell–cell junctions; regulates cell proliferation, migration, and invasion; and promotes tumor development and metastasis. We previously showed serum DSG2 to be a potential biomarker for the diagnosis of esophageal squamous cell carcinoma (ESCC), although the significance and underlying molecular mechanisms were not identified. Here, we found that DSG2 was increased in ESCC tissues compared with adjacent tissues. In addition, we demonstrated that DSG2 promoted ESCC cell migration and invasion. Furthermore, using interactome analysis, we identified serine/threonine‐protein kinase D2 (PRKD2) as a novel DSG2 kinase that mediates the phosphorylation of DSG2 at threonine 730 (T730). Functionally, DSG2 promoted ESCC cell migration and invasion dependent on DSG2‐T730 phosphorylation. Mechanistically, DSG2 T730 phosphorylation activated EGFR, Src, AKT, and ERK signaling pathways. In addition, DSG2 and PRKD2 were positively correlated with each other, and the overall survival time of ESCC patients with high DSG2 and PRKD2 was shorter than that of patients with low DSG2 and PRKD2 levels. In summary, PRKD2 is a novel DSG2 kinase, and PRKD2‐mediated DSG2 T730 phosphorylation promotes ESCC progression. These findings may facilitate the development of future therapeutic agents that target DSG2 and DSG2 phosphorylation. © 2024 The Pathological Society of Great Britain and Ireland.

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Mechanobiology of Cardiac Remodelling in Cardiomyopathy

Randall

Ehler

2023

Cardiac Mechanobiology in Physiology and Disease

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Adrenergic Signaling Strengthens Cardiac Myocyte Cohesion

Cited by 56 publications

References 49 publications

Regulation of cardiac myocyte cohesion and gap junctions via desmosomal adhesion

Regulation of cardiac myocyte cohesion and gap junctions via desmosomal adhesion

Serine/threonine‐protein kinase D2‐mediated phosphorylation of DSG2 threonine 730 promotes esophageal squamous cell carcinoma progression

Mechanobiology of Cardiac Remodelling in Cardiomyopathy

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