title: Adrenergic Signaling Strengthens Cardiac Myocyte Cohesion.
abstract: BACKGROUND
  The sympathetic nervous system is a major mediator of heart function. Intercalated discs composed of desmosomes, adherens junctions, and gap junctions provide the structural backbone for coordinated contraction of cardiac myocytes.
  
  
  OBJECTIVE
  Gap junctions dynamically remodel to adapt to sympathetic signaling. However, it is unknown whether such rapid adaption also occurs for the adhesive function provided by desmosomes and adherens junctions.
  
  
  RESULTS
  Atomic force microscopy revealed that β-adrenergic signaling enhances both the number of desmoglein 2-specific interactions along cell junctions and the mean desmoglein 2-mediated binding forces, whereas N-cadherin-mediated interactions were not affected. This was accompanied by increased cell cohesion in cardiac myocyte cultures and murine heart slices. Enhanced desmoglein 2-positive contacts and increased junction length as revealed by immunofluorescence and electron microscopy reflected cAMP-induced reorganization of intercellular contacts. The mechanism underlying cAMP-mediated strengthening of desmoglein 2 binding was dependent on expression of the intercalated disc plaque protein plakoglobin (Pg) and direct phosphorylation at S665 by protein kinase A: Pg deficiency as well as overexpression of the phospho-deficient Pg-mutant S665A abrogated both cAMP-mediated junctional remodeling and increase of cohesion. Moreover, Pg knockout hearts failed to functionally adapt to adrenergic stimulation.
  
  
  CONCLUSIONS
  Taken together, we provide first evidence for positive adhesiotropy as a new cardiac function of sympathetic signaling. Positive adhesiotropy is dependent on Pg phosphorylation at S665 by protein kinase A. This mechanism may be of high medical relevance because loss of junctional Pg is a hallmark of arrhythmogenic cardiomyopathy.
authors.affiliation: From the Institute of Anatomy and Cell Biology (C.S., F.V., V.R., M.H., M.Y.R., T.K.C., E.H., A.M., A.H., A. Schlipp, V.S., J.W.) and Biomedical Center and Center for Integrated Protein Sciences Munich (A. Schmidt, A.I.), Ludwig-Maximilians-Universität, Germany.
authors.forename: Camilla
authors.initials: C
authors.lastname: Schinner
authors.affiliation: From the Institute of Anatomy and Cell Biology (C.S., F.V., V.R., M.H., M.Y.R., T.K.C., E.H., A.M., A.H., A. Schlipp, V.S., J.W.) and Biomedical Center and Center for Integrated Protein Sciences Munich (A. Schmidt, A.I.), Ludwig-Maximilians-Universität, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Vielmuth
authors.affiliation: From the Institute of Anatomy and Cell Biology (C.S., F.V., V.R., M.H., M.Y.R., T.K.C., E.H., A.M., A.H., A. Schlipp, V.S., J.W.) and Biomedical Center and Center for Integrated Protein Sciences Munich (A. Schmidt, A.I.), Ludwig-Maximilians-Universität, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Rötzer
authors.affiliation: From the Institute of Anatomy and Cell Biology (C.S., F.V., V.R., M.H., M.Y.R., T.K.C., E.H., A.M., A.H., A. Schlipp, V.S., J.W.) and Biomedical Center and Center for Integrated Protein Sciences Munich (A. Schmidt, A.I.), Ludwig-Maximilians-Universität, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hiermaier
authors.affiliation: From the Institute of Anatomy and Cell Biology (C.S., F.V., V.R., M.H., M.Y.R., T.K.C., E.H., A.M., A.H., A. Schlipp, V.S., J.W.) and Biomedical Center and Center for Integrated Protein Sciences Munich (A. Schmidt, A.I.), Ludwig-Maximilians-Universität, Germany.
authors.forename: Mariya Y
authors.initials: MY
authors.lastname: Radeva
authors.affiliation: From the Institute of Anatomy and Cell Biology (C.S., F.V., V.R., M.H., M.Y.R., T.K.C., E.H., A.M., A.H., A. Schlipp, V.S., J.W.) and Biomedical Center and Center for Integrated Protein Sciences Munich (A. Schmidt, A.I.), Ludwig-Maximilians-Universität, Germany.
authors.forename: Thu Kim
authors.initials: TK
authors.lastname: Co
authors.affiliation: From the Institute of Anatomy and Cell Biology (C.S., F.V., V.R., M.H., M.Y.R., T.K.C., E.H., A.M., A.H., A. Schlipp, V.S., J.W.) and Biomedical Center and Center for Integrated Protein Sciences Munich (A. Schmidt, A.I.), Ludwig-Maximilians-Universität, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Hartlieb
authors.affiliation: From the Institute of Anatomy and Cell Biology (C.S., F.V., V.R., M.H., M.Y.R., T.K.C., E.H., A.M., A.H., A. Schlipp, V.S., J.W.) and Biomedical Center and Center for Integrated Protein Sciences Munich (A. Schmidt, A.I.), Ludwig-Maximilians-Universität, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schmidt
authors.affiliation: From the Institute of Anatomy and Cell Biology (C.S., F.V., V.R., M.H., M.Y.R., T.K.C., E.H., A.M., A.H., A. Schlipp, V.S., J.W.) and Biomedical Center and Center for Integrated Protein Sciences Munich (A. Schmidt, A.I.), Ludwig-Maximilians-Universität, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Imhof
authors.affiliation: From the Institute of Anatomy and Cell Biology (C.S., F.V., V.R., M.H., M.Y.R., T.K.C., E.H., A.M., A.H., A. Schlipp, V.S., J.W.) and Biomedical Center and Center for Integrated Protein Sciences Munich (A. Schmidt, A.I.), Ludwig-Maximilians-Universität, Germany.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Messoudi
authors.affiliation: From the Institute of Anatomy and Cell Biology (C.S., F.V., V.R., M.H., M.Y.R., T.K.C., E.H., A.M., A.H., A. Schlipp, V.S., J.W.) and Biomedical Center and Center for Integrated Protein Sciences Munich (A. Schmidt, A.I.), Ludwig-Maximilians-Universität, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Horn
authors.affiliation: From the Institute of Anatomy and Cell Biology (C.S., F.V., V.R., M.H., M.Y.R., T.K.C., E.H., A.M., A.H., A. Schlipp, V.S., J.W.) and Biomedical Center and Center for Integrated Protein Sciences Munich (A. Schmidt, A.I.), Ludwig-Maximilians-Universität, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Schlipp
authors.affiliation: From the Institute of Anatomy and Cell Biology (C.S., F.V., V.R., M.H., M.Y.R., T.K.C., E.H., A.M., A.H., A. Schlipp, V.S., J.W.) and Biomedical Center and Center for Integrated Protein Sciences Munich (A. Schmidt, A.I.), Ludwig-Maximilians-Universität, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Spindler
authors.affiliation: From the Institute of Anatomy and Cell Biology (C.S., F.V., V.R., M.H., M.Y.R., T.K.C., E.H., A.M., A.H., A. Schlipp, V.S., J.W.) and Biomedical Center and Center for Integrated Protein Sciences Munich (A. Schmidt, A.I.), Ludwig-Maximilians-Universität, Germany. jens.waschke@med.uni-muenchen.de.
authors.forename: Jens
authors.initials: J
authors.lastname: Waschke
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051301:Desmoglein 2 / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D005838:Genotype; D066298:In Vitro Techniques; D008297:Male; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018625:Microscopy, Atomic Force; D046529:Microscopy, Electron, Transmission; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D010641:Phenotype; D010766:Phosphorylation; D034622:RNA Interference; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D051185:gamma Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D051301:Desmoglein 2; C495315:Dsg2 protein, mouse; C495293:Jup protein, mouse; D011943:Receptors, Adrenergic, beta; D051185:gamma Catenin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: cardiac function; cell adhesion molecule; desmosome cardiomyopathy; intercellular junction; sympathetic nervous system