title: The "tail" of Connexin43: An unexpected journey from alternative translation to trafficking.
abstract: With each heartbeat, Connexin43 (Cx43) cell-cell communication gap junctions are needed to rapidly spread and coordinate excitation signals for an effective heart contraction. The correct formation and delivery of channels to their respective membrane subdomain is referred to as protein trafficking. Altered Cx43 trafficking is a dangerous complication of diseased myocardium which contributes to the arrhythmias of sudden cardiac death. Cx43 has also been found to regulate many other cellular processes that cannot be explained by cell-cell communication. We recently identified the existence of up to six endogenous internally translated Cx43 N-terminal truncated isoforms from the same full-length mRNA molecule. This is the first evidence that alternative translation is possible for human ion channels and in human heart. Interestingly, we found that these internally translated isoforms, more specifically the 20 kDa isoform (GJA1-20k), is important for delivery of Cx43 to its respective membrane subdomain. This review covers recent advances in Cx43 trafficking and potential importance of alternatively translated Cx43 truncated isoforms. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.
authors.affiliation: Heart Institute and Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Wassim
authors.initials: W
authors.lastname: Basheer
authors.affiliation: Heart Institute and Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Electronic address: Robin.Shaw@cshs.org.
authors.forename: Robin
authors.initials: R
authors.lastname: Shaw
mesh_terms: D000200:Action Potentials; D000818:Animals; D002450:Cell Communication; D018031:Connexin 43 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004705:Endocytosis; D017629:Gap Junctions / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006331:Heart Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism*; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011487:Protein Conformation; D020033:Protein Isoforms; D021381:Protein Transport; D013329:Structure-Activity Relationship
chemical_list: D018031:Connexin 43; C500216:GJA1 protein, human; D020033:Protein Isoforms
keywords: Alternative translation; Arrhythmia; Cardiomyocytes; Connexin43; Targeted Delivery; Trafficking