Regulation of cardiac myocyte cohesion and gap junctions via desmosomal adhesion
- 23 December 2018
- journal article
- research article
- Published by Wiley in Acta Physiologica
- Vol. 226 (2), e13242
- https://doi.org/10.1111/apha.13242
Abstract
Aims Mutations in desmosomal proteins can induce arrhythmogenic cardiomyopathy with life‐threatening arrhythmia. Previous data demonstrated adrenergic signaling to be important to regulate desmosomal cohesion in cardiac myocytes. Here, we investigated how signaling pathways including adrenergic signaling, 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 signaling 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 signaling 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 signaling or SERCA inhibition. These results support the identification of new targets to treat arrhythmogenic cardiomyopathy.Keywords
Funding Information
- Deutsche Forschungsgemeinschaft (WA2474/11-1)
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