title: Interacting Network of the Gap Junction (GJ) Protein Connexin43 (Cx43) is Modulated by Ischemia and Reperfusion in the Heart.
abstract: The coordinated and synchronized cardiac muscle contraction relies on an efficient gap junction-mediated intercellular communication (GJIC) between cardiomyocytes, which involves the rapid anisotropic impulse propagation through connexin (Cx)-containing channels, namely of Cx43, the most abundant Cx in the heart. Expectedly, disturbing mechanisms that affect channel activity, localization and turnover of Cx43 have been implicated in several cardiomyopathies, such as myocardial ischemia. Besides gap junction-mediated intercellular communication, Cx43 has been associated with channel-independent functions, including modulation of cell adhesion, differentiation, proliferation and gene transcription. It has been suggested that the role played by Cx43 is dictated by the nature of the proteins that interact with Cx43. Therefore, the characterization of the Cx43-interacting network and its dynamics is vital to understand not only the molecular mechanisms underlying pathological malfunction of gap junction-mediated intercellular communication, but also to unveil novel and unanticipated biological functions of Cx43. In the present report, we applied a quantitative SWATH-MS approach to characterize the Cx43 interactome in rat hearts subjected to ischemia and ischemia-reperfusion. Our results demonstrate that, in the heart, Cx43 interacts with proteins related with various biological processes such as metabolism, signaling and trafficking. The interaction of Cx43 with proteins involved in gene transcription strengthens the emerging concept that Cx43 has a role in gene expression regulation. Importantly, our data shows that the interactome of Cx43 (Connexome) is differentially modulated in diseased hearts. Overall, the characterization of Cx43-interacting network may contribute to the establishment of new therapeutic targets to modulate cardiac function in physiological and pathological conditions. Data are available via ProteomeXchange with identifier PXD002331.
authors: From the ‡Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Azinhaga de Sta Comba, 3000-354 Coimbra, Portugal;
authors: Tania
authors: T
authors: Martins-Marques
authors: §CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; ¶Faculty of Sciences and Technology, University of Coimbra, 3030-790 Coimbra, Portugal;
authors: Sandra Isabel
authors: SI
authors: Anjo
authors: From the ‡Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Azinhaga de Sta Comba, 3000-354 Coimbra, Portugal;
authors: Paulo
authors: P
authors: Pereira
authors: §CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; ‖Biocant - Biotechnology Innovation Center, 3060-197, Cantanhede, Portugal.
authors: Bruno
authors: B
authors: Manadas
authors: From the ‡Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Azinhaga de Sta Comba, 3000-354 Coimbra, Portugal; hmgirao@fmed.uc.pt.
authors: Henrique
authors: http://orcid.org/0000-0002-5786-8447
authors: H
authors: Girão
mesh_terms: D000818:Animals; D002450:Cell Communication; D002460:Cell Line; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism*; D017629:Gap Junctions / Q000378:metabolism* / Q000648:ultrastructure; D005786:Gene Expression Regulation; D063990:Gene Ontology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D058977:Molecular Sequence Annotation; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000648:ultrastructure; D025941:Protein Interaction Mapping; D051381:Rats; D017208:Rats, Wistar; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D018031:Connexin 43; C580592:Gja1 protein, rat; D008565:Membrane Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D051545:Cyclooxygenase 1; C496513:Ptgs1 protein, rat