4e5f1ec4fbf44f0fba93c592cf343545 pmc_33922534.pdf a5eca5bdbc27cfc1db55601493ecf5d0cb3bfbd9 pmc_33922534.pdf dcc464e943a74fcf541b9998458adc9b6e9c455bd845bf1e50b973ff458e5cf7 pmc_33922534.pdf Title: Connexins in the Heart: Regulation, Function and Involvement in Cardiac Disease Subject: Connexins are a family of transmembrane proteins that play a key role in cardiac physiology. Gap junctional channels put into contact the cytoplasms of connected cardiomyocytes, allowing the existence of electrical coupling. However, in addition to this fundamental role, connexins are also involved in cardiomyocyte death and survival. Thus, chemical coupling through gap junctions plays a key role in the spreading of injury between connected cells. Moreover, in addition to their involvement in cell-to-cell communication, mounting evidence indicates that connexins have additional gap junction-independent functions. Opening of unopposed hemichannels, located at the lateral surface of cardiomyocytes, may compromise cell homeostasis and may be involved in ischemia/reperfusion injury. In addition, connexins located at non-canonical cell structures, including mitochondria and the nucleus, have been demonstrated to be involved in cardioprotection and in regulation of cell growth and differentiation. In this review, we will provide, first, an overview on connexin biology, including their synthesis and degradation, their regulation and their interactions. Then, we will conduct an in-depth examination of the role of connexins in cardiac pathophysiology, including new findings regarding their involvement in myocardial ischemia/reperfusion injury, cardiac fibrosis, gene transcription or signaling regulation. Keywords: connexin; Cx43; gap junction; hemichannel; mitochondria; nucleus; heart; cardiomyocyte Author: Antonio Rodríguez-Sinovas, Jose Antonio Sánchez, Laura Valls-Lacalle, Marta Consegal and Ignacio Ferreira-González Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Fri Apr 23 10:59:17 2021 CEST ModDate: Fri Apr 23 11:16:32 2021 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 64 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 3355679 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- DRZUJM+VnURWPalladioL Type 1 Custom yes yes no 10 0 EBUUZY+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 YDUZVV+URWPalladioL-Bold Type 1 Custom yes yes no 20 0 SEJXPT+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 JXURFX+EURM10 Type 1 Builtin yes yes no 28 0 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RepresentationInformation: pmc_33922534.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2023-03-31 12:09:50 CEST Size: 3355679 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 2517 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: General Aspects of Connexin Biology Destination: section.2 Children: Item: Title: Synthesis and Degradation of Connexins Destination: subsection.2.1 Item: Title: Permeability and Conductance of Connexin Channels Destination: subsection.2.2 Item: Title: Gating Regulation of Connexin Channels Destination: subsection.2.3 Children: Item: Title: Gating by Transjunctional Voltage (Vj) and Transmembrane Potential (Vm) Destination: subsubsection.2.3.1 Item: Title: Gating by Intracellular pH Destination: subsubsection.2.3.2 Item: Title: Calcium- and Calmodulin-Dependent Gating Destination: subsubsection.2.3.3 Item: Title: Regulation by Post-Translational Modifications Destination: subsection.2.4 Children: Item: Title: Phosphorylation Destination: subsubsection.2.4.1 Item: Title: Redox Regulation: S-Nitrosylation and Carbonylation Destination: subsubsection.2.4.2 Item: Title: Acetylation Destination: subsubsection.2.4.3 Item: Title: SUMOylation Destination: subsubsection.2.4.4 Item: Title: Ubiquitination Destination: subsubsection.2.4.5 Item: Title: The Connexin Interactome or Connexome Destination: subsection.2.5 Children: Item: Title: Interactions of Sarcolemmal Connexins with Cytoskeletal Proteins Destination: subsubsection.2.5.1 Item: Title: Interactions of Sarcolemmal Connexins with Other Junctional Proteins Destination: subsubsection.2.5.2 Item: Title: Interactions of Sarcolemmal Connexins with Receptors and Ion Channels Destination: subsubsection.2.5.3 Item: Title: Other Interactors of Sarcolemmal Connexins Destination: subsubsection.2.5.4 Item: Title: Interactions of Mitochondrial Connexins Destination: subsubsection.2.5.5 Item: Title: Cardiac Connexins Destination: section.3 Children: Item: Title: Alterations in Connexin Distribution and Phosphorylation under Pathological Conditions Destination: subsection.3.1 Item: Title: Functions of Cardiac Connexins Destination: subsection.3.2 Children: Item: Title: Sarcolemmal Connexins: Gap Junction-Dependent Role in Cardiac Electrical Coupling Destination: subsubsection.3.2.1 Item: Title: Sarcolemmal Connexins: Gap Junction-Dependent Role in Chemical Coupling Destination: subsubsection.3.2.2 Item: Title: Gap Junction-Independent Functions of Unopposed Sarcolemmal Hemichannels: Involvement in Paracrine Communication and Dysregulation of Cell Homeostasis Destination: subsubsection.3.2.3 Item: Title: Involvement of Sarcolemmal Connexins in Long-Distance Communication through Tunneling Nanotubes and Extracellular Vesicles Destination: subsubsection.3.2.4 Item: Title: Mitochondrial Connexins Destination: subsubsection.3.2.5 Item: Title: Nuclear Connexins Destination: subsubsection.3.2.6 Item: Title: Concluding Remarks Destination: section.4 Item: Title: References Destination: section.4 Info: Title: Connexins in the Heart: Regulation, Function and Involvement in Cardiac Disease Author: Antonio Rodríguez-Sinovas, Jose Antonio Sánchez, Laura Valls-Lacalle, Marta Consegal and Ignacio Ferreira-González Subject: Connexins are a family of transmembrane proteins that play a key role in cardiac physiology. Gap junctional channels put into contact the cytoplasms of connected cardiomyocytes, allowing the existence of electrical coupling. However, in addition to this fundamental role, connexins are also involved in cardiomyocyte death and survival. Thus, chemical coupling through gap junctions plays a key role in the spreading of injury between connected cells. Moreover, in addition to their involvement in cell-to-cell communication, mounting evidence indicates that connexins have additional gap junction-independent functions. Opening of unopposed hemichannels, located at the lateral surface of cardiomyocytes, may compromise cell homeostasis and may be involved in ischemia/reperfusion injury. In addition, connexins located at non-canonical cell structures, including mitochondria and the nucleus, have been demonstrated to be involved in cardioprotection and in regulation of cell growth and differentiation. In this review, we will provide, first, an overview on connexin biology, including their synthesis and degradation, their regulation and their interactions. Then, we will conduct an in-depth examination of the role of connexins in cardiac pathophysiology, including new findings regarding their involvement in myocardial ischemia/reperfusion injury, cardiac fibrosis, gene transcription or signaling regulation. 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