Key result
PKC or adrenergic signaling increases cardiac myocyte cohesion and gap junction localization to preserve conduction.
Why the study?
Mutations in desmosomal proteins induce arrhythmogenic cardiomyopathy with life-threatening arrhythmia, and adrenergic signalling regulates desmosomal cohesion; however, how signalling pathways like adrenergic signalling, PKC, and SERCA regulate desmosomal adhesion and control gap junctions remained unclear.
This preclinical study demonstrates the interplay between gap junctions, desmosomes, and beta-1 adrenergic signaling in cardiac myocytes, highlighting cAMP elevation as a potential therapeutic target for arrhythmogenic cardiomyopathy.
cAMP rescue of cohesion and arrhythmia in HL-1 cells; leaves open whether adrenergic/PKC/SERCA pathways are viable ACM targets in patients.
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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Schinner et al. (2018) studied Arrhythmogenic cardiomyopathy. Signalling pathway modulators (PMA, Trp, thapsigargin, cAMP) was evaluated on Cell cohesion, gap junction localization, and conduction of excitation. Activation of PKC or adrenergic signalling increased cell cohesion and gap junction localization in HL-1 cardiac myocytes, while disruption of cohesion impaired conduction of excitation.
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