title: Antiadrenergic effect of adenosine involves connexin 43 turn-over in H9c2 cells.
abstract: Connexin 43 (Cx43) is the major protein of cardiac ventricular gap junctions and is crucial to cell-cell communication and cardiac function. Several authors report that adrenergic stimulation affects Cx43 expression via protein kinase A (PKA) and MAPK-regulated pathways. Adenosine has been shown to exert direct antiadrenergic effects on the heart, protecting it from toxic effects of overstimulation. The aim of our study was to understand the involvement of Cx43 in the anti-adrenergic effect of adenosine on cardiomyocytes. H9c2 cardiomyoblast cells were treated with isoproterenol alone or in association with adenosine. Isoproterenol and adenosine co-treated H9c2 cells showed an increased amount of Cx43 phosphorylated on Ser368. This effect was adenosine A1 receptor-dependent via the activation of the protein kinase C (PKC). Interestingly, the phosphorylation of Cx43 facilitated the degradation of Cx43 through the ubiquitin-proteasome system, as demonstrated by the immunoprecipitation of pCx43 with ubiquitin. On the basis of these results we can hypothesize that the activation of PKC after adenosine A1 receptor stimulation increases Cx43 phosphorylation that is necessary for its ubiquitination and then degradation via the proteasome system. These data better underline new mechanism at the basis of antiadrenergic effects of adenosine.
authors.affiliation: Department of Pharmacy, University of Salerno, Fisciano, Salerno 84084, Italy. apopolo@unisa.it
authors.forename: Ada
authors.initials: A
authors.lastname: Popolo
authors.forename: Silvana
authors.initials: S
authors.lastname: Morello
authors.forename: Rosalinda
authors.initials: R
authors.lastname: Sorrentino
authors.forename: Aldo
authors.initials: A
authors.lastname: Pinto
mesh_terms: D000241:Adenosine / Q000494:pharmacology*; D018674:Adrenergic Antagonists / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D018031:Connexin 43 / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D018674:Adrenergic Antagonists; D018031:Connexin 43; D043682:Receptor, Adenosine A1; D025801:Ubiquitin; D012694:Serine; D011493:Protein Kinase C; D046988:Proteasome Endopeptidase Complex; D000241:Adenosine; D007545:Isoproterenol
keywords: Adenosine; Connexin 43; H9c2; Isoproterenol