{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T07:22:41Z","timestamp":1777620161678,"version":"3.51.4"},"reference-count":50,"publisher":"Portland Press Ltd.","issue":"3","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2015,6,1]]},"abstract":"<jats:p>The main function of the heart is to pump blood to the different parts of the organism, a task that is efficiently accomplished through proper electric and metabolic coupling between cardiac cells, ensured by gap junctions (GJ). Cardiomyocytes are the major cell population in the heart, and as cells with low mitotic activity, are highly dependent upon mechanisms of protein degradation. In the heart, both the ubiquitin-proteasome system (UPS) and autophagy participate in the fine-tune regulation of cardiac remodelling and function, either in physiological or pathological conditions. Indeed, besides controlling cardiac signalling pathways, UPS and autophagy have been implicated in the turnover of several myocardial proteins. Degradation of Cx43, the major ventricular GJ protein, has been associated to up-regulation of autophagy at the onset of heart ischemia and ischemia\/reperfusion (I\/R), which can have profound implications upon cardiac function. In this review, we present recent studies devoted to the involvement of autophagy and UPS in heart homoeostasis, with a particular focus on GJ.<\/jats:p>","DOI":"10.1042\/bst20150046","type":"journal-article","created":{"date-parts":[[2015,5,26]],"date-time":"2015-05-26T15:15:34Z","timestamp":1432653334000},"page":"476-481","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["To beat or not to beat: degradation of Cx43 imposes the heart rhythm"],"prefix":"10.1042","volume":"43","author":[{"given":"T\u00e2nia","family":"Martins-Marques","sequence":"first","affiliation":[{"name":"Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Azinhaga de Sta Comba, 3000-354 Coimbra, Portugal"}]},{"given":"Steve","family":"Catarino","sequence":"additional","affiliation":[{"name":"Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Azinhaga de Sta Comba, 3000-354 Coimbra, Portugal"}]},{"given":"Carla","family":"Marques","sequence":"additional","affiliation":[{"name":"Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Azinhaga de Sta Comba, 3000-354 Coimbra, Portugal"}]},{"given":"Paulo","family":"Pereira","sequence":"additional","affiliation":[{"name":"Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Azinhaga de Sta Comba, 3000-354 Coimbra, Portugal"}]},{"given":"Henrique","family":"Gir\u00e3o","sequence":"additional","affiliation":[{"name":"Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Azinhaga de Sta Comba, 3000-354 Coimbra, Portugal"}]}],"member":"288","published-online":{"date-parts":[[2015,6,1]]},"reference":[{"key":"2021111719362051300_B1","first-page":"9","article-title":"Autophagy and the ubiquitin-proteasome system in cardiac dysfunction","volume":"52","author":"Zheng","year":"2010","journal-title":"Panminerva Med."},{"key":"2021111719362051300_B2","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1016\/j.bbrc.2007.04.015","article-title":"A proteomics approach to identify the ubiquitinated proteins in mouse heart","volume":"357","author":"Jeon","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021111719362051300_B3","doi-asserted-by":"crossref","DOI":"10.1089\/dna.2014.2765","article-title":"Autophagy and ubiquitination in cardiovascular diseases","author":"Martins-Marques","year":"2015","journal-title":"DNA Cell Biol."},{"key":"2021111719362051300_B4","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1016\/j.molmed.2013.01.005","article-title":"Breaking down protein degradation mechanisms in cardiac muscle","volume":"19","author":"Lyon","year":"2013","journal-title":"Trends Mol. Med."},{"key":"2021111719362051300_B5","doi-asserted-by":"publisher","first-page":"3070","DOI":"10.1161\/CIRCULATIONAHA.107.763870","article-title":"Intracellular protein aggregation is a proximal trigger of cardiomyocyte autophagy","volume":"117","author":"Tannous","year":"2008","journal-title":"Circulation"},{"key":"2021111719362051300_B6","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/j.cardiores.2003.11.035","article-title":"Role of gap junctions in the propagation of the cardiac action potential","volume":"62","author":"Rohr","year":"2004","journal-title":"Cardiovasc. Res."},{"key":"2021111719362051300_B7","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1152\/physiol.00038.2012","article-title":"Proteins and mechanisms regulating gap-junction assembly, internalization, and degradation","volume":"28","author":"Thevenin","year":"2013","journal-title":"Physiology (Bethesda)."},{"key":"2021111719362051300_B8","doi-asserted-by":"publisher","first-page":"1423","DOI":"10.1016\/j.febslet.2014.01.049","article-title":"Specific Cx43 phosphorylation events regulate gap junction turnover in\u00a0vivo","volume":"588","author":"Solan","year":"2014","journal-title":"FEBS Lett."},{"key":"2021111719362051300_B9","doi-asserted-by":"publisher","first-page":"26399","DOI":"10.1074\/jbc.270.44.26399","article-title":"The gap junction protein connexin43 is degraded via the ubiquitin proteasome pathway","volume":"270","author":"Laing","year":"1995","journal-title":"J. Biol. Chem."},{"key":"2021111719362051300_B10","doi-asserted-by":"publisher","first-page":"2156","DOI":"10.1091\/mbc.E11-10-0844","article-title":"Autophagy modulates dynamics of connexins at the plasma membrane in a ubiquitin-dependent manner","volume":"23","author":"Bejarano","year":"2012","journal-title":"Mol. Biol. Cell"},{"key":"2021111719362051300_B11","doi-asserted-by":"publisher","first-page":"35857","DOI":"10.1074\/jbc.R300018200","article-title":"Non-traditional functions of ubiquitin and ubiquitin-binding proteins","volume":"278","author":"Schnell","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2021111719362051300_B12","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1053\/jhep.2002.30316","article-title":"Ubiquitin-mediated degradation of cellular proteins in health and disease","volume":"35","author":"Ciechanover","year":"2002","journal-title":"Hepatology"},{"key":"2021111719362051300_B13","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/1741-7007-10-23","article-title":"Generation and physiological roles of linear ubiquitin chains","volume":"10","author":"Walczak","year":"2012","journal-title":"BMC Biol."},{"key":"2021111719362051300_B14","doi-asserted-by":"publisher","first-page":"15722","DOI":"10.1073\/pnas.1308014110","article-title":"Lysine 63-linked polyubiquitination is required for EGF receptor degradation","volume":"110","author":"Huang","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021111719362051300_B15","doi-asserted-by":"publisher","first-page":"4629","DOI":"10.1096\/fj.13-248963","article-title":"AMSH-mediated deubiquitination of Cx43 regulates internalization and degradation of gap junctions","volume":"28","author":"Ribeiro-Rodrigues","year":"2014","journal-title":"FASEB J."},{"key":"2021111719362051300_B16","doi-asserted-by":"publisher","first-page":"832704","DOI":"10.1155\/2014\/832704","article-title":"The role of the selective adaptor p62 and ubiquitin-like proteins in autophagy","volume":"2014","author":"Lippai","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"2021111719362051300_B17","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1146\/annurev.biochem.78.081507.101607","article-title":"Recognition and processing of ubiquitin-protein conjugates by the proteasome","volume":"78","author":"Finley","year":"2009","journal-title":"Annu. Rev. Biochem."},{"key":"2021111719362051300_B18","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1016\/j.cmet.2007.09.009","article-title":"The E3 Ligase MuRF1 degrades myosin heavy chain protein in dexamethasone-treated skeletal muscle","volume":"6","author":"Clarke","year":"2007","journal-title":"Cell Metab."},{"key":"2021111719362051300_B19","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1016\/j.jmb.2005.05.021","article-title":"MURF-1 and MURF-2 target a specific subset of myofibrillar proteins redundantly: towards understanding MURF-dependent muscle ubiquitination","volume":"350","author":"Witt","year":"2005","journal-title":"J. Mol. Biol."},{"key":"2021111719362051300_B20","doi-asserted-by":"publisher","first-page":"18135","DOI":"10.1073\/pnas.0404341102","article-title":"Muscle-specific RING finger 1 is a bona fide ubiquitin ligase that degrades cardiac troponin I","volume":"101","author":"Kedar","year":"2004","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021111719362051300_B21","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1016\/j.ajpath.2010.11.049","article-title":"The ubiquitin ligase MuRF1 protects against cardiac ischemia\/reperfusion injury by its proteasome-dependent degradation of phospho-c-Jun","volume":"178","author":"Li","year":"2011","journal-title":"Am. J. Pathol."},{"key":"2021111719362051300_B22","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1016\/j.tcm.2012.05.015","article-title":"p62 stages an interplay between the ubiquitin-proteasome system and autophagy in the heart of defense against proteotoxic stress","volume":"21","author":"Su","year":"2012","journal-title":"Trends Cardiovasc. Med."},{"key":"2021111719362051300_B23","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1038\/ncb2788","article-title":"Emerging regulation and functions of autophagy","volume":"15","author":"Boya","year":"2013","journal-title":"Nat. Cell. Biol."},{"key":"2021111719362051300_B24","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1038\/cr.2013.168","article-title":"The machinery of macroautophagy","volume":"24","author":"Feng","year":"2013","journal-title":"Cell Res."},{"key":"2021111719362051300_B25","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1038\/ncb2152","article-title":"AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1","volume":"13","author":"Kim","year":"2011","journal-title":"Nat. Cell. Biol."},{"key":"2021111719362051300_B26","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1146\/annurev-physiol-021909-135757","article-title":"Autophagy during cardiac stress: joys and frustrations of autophagy","volume":"72","author":"Gottlieb","year":"2010","journal-title":"Annu. Rev. Physiol."},{"key":"2021111719362051300_B27","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1093\/cvr\/cvr358","article-title":"Autophagy as a therapeutic target for ischaemia\/reperfusion injury? Concepts, controversies, and challenges","volume":"94","author":"Przyklenk","year":"2012","journal-title":"Cardiovasc. Res."},{"key":"2021111719362051300_B28","doi-asserted-by":"publisher","first-page":"902","DOI":"10.1038\/35022595","article-title":"Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice","volume":"406","author":"Tanaka","year":"2000","journal-title":"Nature"},{"key":"2021111719362051300_B29","doi-asserted-by":"publisher","first-page":"29776","DOI":"10.1074\/jbc.M603783200","article-title":"Enhancing macroautophagy protects against ischemia\/reperfusion injury in cardiac myocytes","volume":"281","author":"Hamacher-Brady","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2021111719362051300_B30","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1161\/01.RES.0000261924.76669.36","article-title":"Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy","volume":"100","author":"Matsui","year":"2007","journal-title":"Circ. Res."},{"key":"2021111719362051300_B31","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.ydbio.2010.12.024","article-title":"Developmental regulation of MURF ubiquitin ligases and autophagy proteins nbr1, p62\/SQSTM1 and LC3 during cardiac myofibril assembly and turnover","volume":"351","author":"Perera","year":"2010","journal-title":"Dev. Biol."},{"key":"2021111719362051300_B32","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.yjmcc.2003.10.006","article-title":"Functional role of connexin43 gap junction channels in adult mouse heart assessed by inducible gene deletion","volume":"36","author":"Eckardt","year":"2004","journal-title":"J. Mol. Cell. Cardiol."},{"key":"2021111719362051300_B33","doi-asserted-by":"publisher","first-page":"3587","DOI":"10.1016\/j.yexcr.2009.10.003","article-title":"Eps15 interacts with ubiquitinated Cx43 and mediates its internalization","volume":"315","author":"Girao","year":"2009","journal-title":"Exp. Cell. Res."},{"key":"2021111719362051300_B34","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1042\/BJ20102059","article-title":"Ubiquitin-mediated internalization of connexin43 is independent of the canonical endocytic tyrosine-sorting signal","volume":"437","author":"Catarino","year":"2011","journal-title":"Biochem. J."},{"key":"2021111719362051300_B35","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1161\/01.RES.87.8.656","article-title":"Dephosphorylation and intracellular redistribution of ventricular connexin43 during electrical uncoupling induced by ischemia","volume":"87","author":"Beardslee","year":"2000","journal-title":"Circ. Res."},{"key":"2021111719362051300_B36","doi-asserted-by":"crossref","DOI":"10.1042\/BJ20141370","article-title":"Ischemia-induced autophagy leads to degradation of gap junction protein Connexin43 in cardiomyocytes","author":"Martins-Marques","year":"2015","journal-title":"Biochem. J."},{"key":"2021111719362051300_B37","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1016\/j.hrthm.2011.11.048","article-title":"The molecular mechanisms of gap junction remodeling","volume":"9","author":"Duffy","year":"2011","journal-title":"Heart Rhythm."},{"key":"2021111719362051300_B38","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1093\/cvr\/cvm083","article-title":"Gap junction remodelling in human heart failure is associated with increased interaction of connexin43 with ZO-1","volume":"77","author":"Bruce","year":"2008","journal-title":"Cardiovasc. Res."},{"key":"2021111719362051300_B39","doi-asserted-by":"publisher","first-page":"1103","DOI":"10.1161\/CIRCRESAHA.108.190454","article-title":"Structural and molecular mechanisms of gap junction remodeling in epicardial border zone myocytes following myocardial infarction","volume":"104","author":"Kieken","year":"2009","journal-title":"Circ. Res."},{"key":"2021111719362051300_B40","doi-asserted-by":"publisher","first-page":"3435","DOI":"10.1242\/jcs.03089","article-title":"Analysis of Connexin43 phosphorylated at S325, S328 and S330 in normoxic and ischemic heart","volume":"119","author":"Lampe","year":"2006","journal-title":"J. Cell. Sci."},{"key":"2021111719362051300_B41","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1111\/j.1540-8167.1999.tb00645.x","article-title":"Heterogeneous loss of connexin43 protein in ischemic dog hearts","volume":"10","author":"Huang","year":"1999","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"2021111719362051300_B42","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1111\/j.1365-2818.1993.tb03308.x","article-title":"Intercellular junctions and the application of microscopical techniques: the cardiac gap junction as a case model","volume":"169","author":"Severs","year":"1993","journal-title":"J. Microsc."},{"key":"2021111719362051300_B43","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1536\/jhj.45.1007","article-title":"Down-regulation of connexin43 in early myocardial ischemia and protective effect by ischemic preconditioning in rat hearts in\u00a0vivo","volume":"45","author":"Hatanaka","year":"2004","journal-title":"Jpn. Heart. J."},{"key":"2021111719362051300_B44","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1111\/tra.12169","article-title":"A 14\u20133-3 mode-1 binding motif initiates gap junction internalization during acute cardiac ischemia","volume":"15","author":"Smyth","year":"2014","journal-title":"Traffic"},{"key":"2021111719362051300_B45","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1161\/01.RES.83.6.629","article-title":"Rapid turnover of connexin43 in the adult rat heart","volume":"83","author":"Beardslee","year":"1998","journal-title":"Circ. Res."},{"key":"2021111719362051300_B46","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1016\/S0008-6363(98)00060-1","article-title":"Proteolysis of connexin43-containing gap junctions in normal and heat-stressed cardiac myocytes","volume":"38","author":"Laing","year":"1998","journal-title":"Cardiovasc. Res."},{"key":"2021111719362051300_B47","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1007\/s11010-006-9166-y","article-title":"Remodeling of connexin 43 in the diabetic rat heart","volume":"290","author":"Lin","year":"2006","journal-title":"Mol. Cell. Biochem."},{"key":"2021111719362051300_B48","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.ejphar.2013.06.019","article-title":"Antiadrenergic effect of adenosine involves connexin 43 turn-over in H9c2 cells","volume":"715","author":"Popolo","year":"2013","journal-title":"Eur. J. Pharmacol."},{"key":"2021111719362051300_B49","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.1161\/CIRCRESAHA.108.182147","article-title":"Ultrastructure and regulation of lateralized connexin43 in the failing heart","volume":"106","author":"Hesketh","year":"2010","journal-title":"Circ. Res."},{"key":"2021111719362051300_B50","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1016\/j.cardiores.2003.11.039","article-title":"Gap junction-mediated spread of cell injury and death during myocardial ischemia-reperfusion","volume":"61","author":"Garcia-Dorado","year":"2004","journal-title":"Cardiovasc. Res."}],"container-title":["Biochemical Society Transactions"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemsoctrans\/article-pdf\/43\/3\/476\/486495\/bst0430476.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemsoctrans\/article-pdf\/43\/3\/476\/486495\/bst0430476.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,17]],"date-time":"2021-11-17T21:52:00Z","timestamp":1637185920000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemsoctrans\/article\/43\/3\/476\/65052\/To-beat-or-not-to-beat-degradation-of-Cx43-imposes"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,6,1]]},"references-count":50,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2015,6,1]]},"published-print":{"date-parts":[[2015,6,1]]}},"URL":"https:\/\/doi.org\/10.1042\/bst20150046","relation":{},"ISSN":["0300-5127","1470-8752"],"issn-type":[{"value":"0300-5127","type":"print"},{"value":"1470-8752","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,6,1]]}}}