CONNEXONS IN CARDIOVASCULAR CELL COMMUNICATION

Summary

Principal Investigator: Eric C Beyer
Abstract: DESCRIPTION (provided by applicant): Atrial fibrillation is the most common arrhythmia in man and confers a significant morbidity and increased risk of mortality. Gap junction channels are likely to play significant roles in the stabilization and maintenance of atrial fibrillation, since atrial fibrillation is associated with remodeling of connections between atrial myocytes and altered electrical conduction. These channels (made of connexin subunits, CX) provide a pathway for direct intercellular passage of ions and small molecules facilitating cardiac electrical conduction and coordination of the responses of cardiovascular cells to intracellular signals. Two major connexins (CX40 and CX43) are expressed in the atrium. A variety of provocative studies suggest that alterations of CX40 (including reduced levels, heterogeneity of distribution, and mutations) contribute to the pathogenesis of atrial fibrillation. A series of experiments are proposed: (1) to test the hypothesis that alterations of CX40 alone or relative to CX43 are present in atrial tissue from patients with atrial fibrillation, and (2) to use expression systems to test how these alterations can affect intercellular communication. The results of the proposed experiments will clarify the role of gap junctions in cardiac arrhythmias. They will also elucidate the basic cellular biology and physiology of gap junction-mediated intercellular communication. PUBLIC HEALTH RELEVANCE: The normal functioning of the heart depends on passage of electrical current between cells and is facilitated by intercellular channels contained within structures known as gap junctions. Disturbances of electrical conduction lead to abnormal heart rhythms such as atrial fibrillation. Our studies will clarify how abnormalities of the subunit gap junction proteins lead to arrhythmias such as atrial fibrillation.
Funding Period: 1998-09-01 - 2014-05-31
more information: NIH RePORT

Top Publications

  1. pmc N-terminal residues in Cx43 and Cx40 determine physiological properties of gap junction channels, but do not influence heteromeric assembly with each other or with Cx26
    Joanna Gemel
    Department of Pediatrics, Section of Hematology Oncology and Stem Cell Transplantation, University of Chicago, IL 60637 1470, USA
    J Cell Sci 119:2258-68. 2006
  2. pmc c-Src kinase inhibition reduces arrhythmia inducibility and connexin43 dysregulation after myocardial infarction
    Cody A Rutledge
    Department of Physiology, University of Illinois at Chicago, Chicago, Illinois Lifespan Cardiovascular Institute, The Warren Alpert School of Medicine of Brown University, and the Providence Veterans Administration Medical Center, Providence Rhode Island
    J Am Coll Cardiol 63:928-34. 2014
  3. pmc Interfering amino terminal peptides and functional implications for heteromeric gap junction formation
    Eric C Beyer
    Department of Pediatrics, University of Chicago Chicago, IL, USA
    Front Pharmacol 4:67. 2013
  4. pmc c-Jun N-terminal kinase activation contributes to reduced connexin43 and development of atrial arrhythmias
    Jiajie Yan
    Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
    Cardiovasc Res 97:589-97. 2013
  5. pmc Critical role of the first transmembrane domain of Cx26 in regulating oligomerization and function
    Oscar Jara
    Centro Interdisciplinario de Neurociencias de Valparaíso, Universidad de Valparaiso, Valparaiso, Chile
    Mol Biol Cell 23:3299-311. 2012
  6. pmc Inducible coexpression of connexin37 or connexin40 with connexin43 selectively affects intercellular molecular transfer
    Joanna Gemel
    Department of Pediatrics, University of Chicago, Chicago, IL 60637, USA
    J Membr Biol 245:231-41. 2012
  7. pmc Cytoplasmic amino acids within the membrane interface region influence connexin oligomerization
    Tekla D Smith
    Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Whitehead Biomedical Research Building, Atlanta, GA 30022, USA
    J Membr Biol 245:221-30. 2012
  8. pmc Structural organization of intercellular channels II. Amino terminal domain of the connexins: sequence, functional roles, and structure
    Eric C Beyer
    Department of Pediatrics, University of Chicago, Chicago, IL 60637, USA
    Biochim Biophys Acta 1818:1823-30. 2012
  9. pmc Atomic force microscopy of Connexin40 gap junction hemichannels reveals calcium-dependent three-dimensional molecular topography and open-closed conformations of both the extracellular and cytoplasmic faces
    Michael J Allen
    Section of Pulmonary Critical Care, Center for Nanomedicine, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA
    J Biol Chem 286:22139-46. 2011
  10. pmc Autophagy: a pathway that contributes to connexin degradation
    Alexandra Lichtenstein
    Department of Pediatrics, University of Chicago, Chicago, IL 60637, USA
    J Cell Sci 124:910-20. 2011

Research Grants

  1. INTEGRATED MECHANISMS OF CARDIAC MALADAPTATION
    R John Solaro; Fiscal Year: 2013
  2. From human keratinocytes to biological pacemakers
    Ira S Cohen; Fiscal Year: 2013
  3. Sodium Channels and Cardiac Arrhythmias
    Isabelle Deschenes; Fiscal Year: 2013
  4. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
  5. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
  6. STRUCTURE AND DYNAMICS OF CONNEXIN26 GAP JUNCTIONS
    Gina E Sosinsky; Fiscal Year: 2013
  7. Gap Junctional Patterning in Arrhythmic Heart
    Robert G Gourdie; Fiscal Year: 2013
  8. ION CHANNEL REGULATION AND MODULATION IN CARDIAC MUSCLE
    Jeanne M Nerbonne; Fiscal Year: 2013
  9. Modeling Cardiac Impulse Propagation at the Microscale
    Craig S Henriquez; Fiscal Year: 2013
  10. Cyclic nucleotide permeability of connexin mutants related to genetic disease
    Virginijus Valiunas; Fiscal Year: 2013

Detail Information

Publications18

  1. pmc N-terminal residues in Cx43 and Cx40 determine physiological properties of gap junction channels, but do not influence heteromeric assembly with each other or with Cx26
    Joanna Gemel
    Department of Pediatrics, Section of Hematology Oncology and Stem Cell Transplantation, University of Chicago, IL 60637 1470, USA
    J Cell Sci 119:2258-68. 2006
    ....
  2. pmc c-Src kinase inhibition reduces arrhythmia inducibility and connexin43 dysregulation after myocardial infarction
    Cody A Rutledge
    Department of Physiology, University of Illinois at Chicago, Chicago, Illinois Lifespan Cardiovascular Institute, The Warren Alpert School of Medicine of Brown University, and the Providence Veterans Administration Medical Center, Providence Rhode Island
    J Am Coll Cardiol 63:928-34. 2014
    ..The aim of this study was to evaluate the role of tyrosine kinase cellular-Src (c-Src) inhibition on connexin43 (Cx43) regulation in a mouse model of myocardial infarction (MI)...
  3. pmc Interfering amino terminal peptides and functional implications for heteromeric gap junction formation
    Eric C Beyer
    Department of Pediatrics, University of Chicago Chicago, IL, USA
    Front Pharmacol 4:67. 2013
    ..These findings present unique functional implications about the heteromeric interactions between Cx43 and Cx40 that may influence cardiac conduction in atrial myocardium and the specialized conduction system...
  4. pmc c-Jun N-terminal kinase activation contributes to reduced connexin43 and development of atrial arrhythmias
    Jiajie Yan
    Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
    Cardiovasc Res 97:589-97. 2013
    ..However, the contribution of JNK to AF remains unknown. Thus, we assessed the role of JNK in remodelling of gap junction connexin43 (Cx43) and development of AF...
  5. pmc Critical role of the first transmembrane domain of Cx26 in regulating oligomerization and function
    Oscar Jara
    Centro Interdisciplinario de Neurociencias de Valparaíso, Universidad de Valparaiso, Valparaiso, Chile
    Mol Biol Cell 23:3299-311. 2012
    ..Moreover, Cx26 oligomerization appears dependent on transient TM1 dimerization as an intermediate step...
  6. pmc Inducible coexpression of connexin37 or connexin40 with connexin43 selectively affects intercellular molecular transfer
    Joanna Gemel
    Department of Pediatrics, University of Chicago, Chicago, IL 60637, USA
    J Membr Biol 245:231-41. 2012
    ..These data show that induced expression of either Cx37 or Cx40 in Cx43-expressing cells can selectively alter the intercellular exchange of some molecules without affecting the transfer of others...
  7. pmc Cytoplasmic amino acids within the membrane interface region influence connexin oligomerization
    Tekla D Smith
    Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Whitehead Biomedical Research Building, Atlanta, GA 30022, USA
    J Membr Biol 245:221-30. 2012
    ....
  8. pmc Structural organization of intercellular channels II. Amino terminal domain of the connexins: sequence, functional roles, and structure
    Eric C Beyer
    Department of Pediatrics, University of Chicago, Chicago, IL 60637, USA
    Biochim Biophys Acta 1818:1823-30. 2012
    ..This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics...
  9. pmc Atomic force microscopy of Connexin40 gap junction hemichannels reveals calcium-dependent three-dimensional molecular topography and open-closed conformations of both the extracellular and cytoplasmic faces
    Michael J Allen
    Section of Pulmonary Critical Care, Center for Nanomedicine, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA
    J Biol Chem 286:22139-46. 2011
    ....
  10. pmc Autophagy: a pathway that contributes to connexin degradation
    Alexandra Lichtenstein
    Department of Pediatrics, University of Chicago, Chicago, IL 60637, USA
    J Cell Sci 124:910-20. 2011
    ..These results demonstrate that autophagy can regulate cellular levels of wild-type connexins and imply that the persistence of accumulations of CX50P88S results from insufficient degradation capacity of constitutive autophagy...
  11. pmc Different domains are critical for oligomerization compatibility of different connexins
    Agustin D Martinez
    Centro Interdisciplinario de Neurociencias de Valparaíso, Departamento de Neurociencias, Universidad de Vaparaíso, Valparaíso 2360102, Chile
    Biochem J 436:35-43. 2011
    ..However, motifs in different domains may determine oligomerization compatibility in members of different connexin subfamilies...
  12. pmc Connexin40 and connexin43 determine gating properties of atrial gap junction channels
    Xianming Lin
    Department of Pharmacology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA
    J Mol Cell Cardiol 48:238-45. 2010
    ..Co-expression of Cx40 accounts for most, but not all, of the differences in the V(j)-dependent gating properties between atrium and ventricle that may play a role in the genesis of slow myocardial conduction and arrhythmias...
  13. pmc The N terminus of connexin37 contains an alpha-helix that is required for channel function
    John W Kyle
    Department of Medicine Section of Cardiology, University of Chicago, Chicago, Illinois 60637 1470, USA
    J Biol Chem 284:20418-27. 2009
    ..Taken together, our data suggest that the alpha-helical structure of the connexin37 N terminus may be dispensable for protein localization, but it is required for channel and hemichannel function...
  14. pmc An intact connexin N-terminus is required for function but not gap junction formation
    John W Kyle
    Department of Medicine, Section of Cardiology, University of Chicago, Chicago, IL 60637, USA
    J Cell Sci 121:2744-50. 2008
    ..We conclude that as much as half the length of the connexin N-terminus can be deleted without affecting formation of gap junction plaques, but an intact N-terminus is required for hemichannel gating and intercellular communication...
  15. pmc Cataracts are caused by alterations of a critical N-terminal positive charge in connexin50
    Bettina C Thomas
    Department of Pediatrics, University of Chicago, Chicago, Illinois 60637 1470, USA
    Invest Ophthalmol Vis Sci 49:2549-56. 2008
    ....
  16. pmc Cx30.2 can form heteromeric gap junction channels with other cardiac connexins
    Joanna Gemel
    University of Chicago, Department of Pediatrics MC 4060, 5841 S Maryland Avenue, Chicago, IL 60637 1470, USA
    Biochem Biophys Res Commun 369:388-94. 2008
    ..Our data suggest that connexin30.2 can form heteromers with the other cardiac connexins and that mixed channel formation will influence the gating properties of gap junctions in cardiac regions that co-express these connexins...
  17. pmc Connexin43 increases the sensitivity of prostate cancer cells to TNFalpha-induced apoptosis
    Min Wang
    Department of Pediatrics, Section of Hematology Oncology and Stem Cell Transplantation, University of Chicago, Chicago, IL 60637, USA
    J Cell Sci 120:320-9. 2007
    ..These results demonstrate that TNFalpha induces apoptosis in LNCaP cells by signaling through TNFalpha receptor 1 and that expression of functional Cx43 gap junction channels increases their sensitivity to TNFalpha...
  18. pmc Atrial fibrillation-associated connexin40 mutants make hemichannels and synergistically form gap junction channels with novel properties
    Dakshesh Patel
    Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, United States
    FEBS Lett 588:1458-64. 2014
    ..While co-expression of the two mutations had similar effects on Vj gating, it synergistically increased γj by 50%. Unlike WTCx40 or M163V, G38D induced activity of a dominant 271 pS hemichannel...

Research Grants30

  1. INTEGRATED MECHANISMS OF CARDIAC MALADAPTATION
    R John Solaro; Fiscal Year: 2013
    ..Studies proposed here offer the potential for novel diagnostic procedures early in the progression of the disorders, and targets for novel therapies. (End of Abstract) ..
  2. From human keratinocytes to biological pacemakers
    Ira S Cohen; Fiscal Year: 2013
    ..If the HFKT-pacemaker functions well in the canine heart, a future goal would be to advance this novel autologous, cellular approach towards clinical deployment. ..
  3. Sodium Channels and Cardiac Arrhythmias
    Isabelle Deschenes; Fiscal Year: 2013
    ..This is crucial for cardiologists to select family members who will more likely benefit from an expensive and risky therapy, the implanted defibrillator. A gene therapy approach will also be developed to treat arrhythmias. ..
  4. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
    ..3. Recruit promising junior investigators and provide mentoring by established NIH-funded researchers. 4. Support a multidisciplinary research program led by junior investigators in translational infectious diseases immunology. ..
  5. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  6. STRUCTURE AND DYNAMICS OF CONNEXIN26 GAP JUNCTIONS
    Gina E Sosinsky; Fiscal Year: 2013
    ..The proposed research is significant because results will be useful in defining better drugs and other therapeutics that potentially ameliorate connexin-related diseases. ..
  7. Gap Junctional Patterning in Arrhythmic Heart
    Robert G Gourdie; Fiscal Year: 2013
    ..This project will deliver new insights on the function of a protein essential to a stable heartbeat called connexin43. The project aims to provide novel approaches to the prevention and treatment of heart attacks. ..
  8. ION CHANNEL REGULATION AND MODULATION IN CARDIAC MUSCLE
    Jeanne M Nerbonne; Fiscal Year: 2013
    ....
  9. Modeling Cardiac Impulse Propagation at the Microscale
    Craig S Henriquez; Fiscal Year: 2013
    ..abstract_text> ..
  10. Cyclic nucleotide permeability of connexin mutants related to genetic disease
    Virginijus Valiunas; Fiscal Year: 2013
    ..The results of the proposed research will establish a baseline for understanding the role of perm-selectivity as a potential determinant of disease states such as oculodentodigital dysplasia and atrial fibrillation. ..
  11. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  12. Connexin Distribution in Physiological Versus Pathological Cardiac Hypertrophy
    Michael R Zile; Fiscal Year: 2013
    ..pathological hypertrophy, with ex- tensively characterized cytoskeletal properties in each setting. ..