Connexins and Heart Function

Summary

Principal Investigator: Feliksas Bukauskas
Abstract: DESCRIPTION (provided by applicant): Gap junction (GJ) channels, which are multimers of connexin (Cx) proteins, mediate direct cell-cell transfer of ions and metabolites and are required for propagation of excitation in the heart. This project is based on our recent discovery of a new cardiac Cx (mCx30.2) and data showing that knockout of mCx30.2 accelerates conduction in the atrioventricular (AV) node and reduces the Wenckebach period. mCx30.2 is found to be expressed not only in the heart but also in many other organs and tissues including neurons. The experiments will combine immunohistochemical and biophysical characterization of Cx-based channels in cardiomyocytes and exogenously expressed in mammalian cell lines. Specific Aim 1 focuses on gating and permeability properties of GJ channels and unapposed hemichannels formed of mCx30.2. We will determine whether two gates, 'fast'and 'slow', are also present in mCx30.2 GJs. We will determine the extent to which mCx30.2 hemichannels influence metabolic exchange across the plasma membrane. In Specific Aim 2, we will determine gating and permeability properties of heterotypic gap junction channels formed from cardiac Cxs. To establish whether mCx30.2 exhibits a dominant negative effect on junctional communication and slows atrioventricular conduction, we will determine whether mCx30.2 together with other cardiac connexins can oligomerize into heteromeric connexons (hemichannels) and whether these connexons can form functional heteromeric hemichannels and cell-cell channels. To determine the domains underlying the distinctive biophysical properties of mCx30.2 channels, we will examine chimeras formed of mCx30.2 and Cx43. In Specific Aim 3, we will examine an expression pattern of mCx30.2 and other cardiac Cxs in the AV-nodal region and correlate these data with measurements of passive electrical properties, excitability, refractoriness and resting potential to find why deletion of mCx30.2 accelerates AV conduction and reduces the Wenckebach period. In isolated cardiomyocytes of wild type and transfected with mCx30.2, we will examine whether homotypic, heterotypic and heteromeric GJ channels containing mCx30.2 form and function. We will determine whether mCx30.2 hemichannels are functional in cardiomyocytes and whether they contribute to slow propagation of excitation in the AV node and protection of ventricles from over excitation during atrial tachyarrhythmia.
Funding Period: ----------------2007 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Neurons and β-cells of the pancreas express connexin36, forming gap junction channels that exhibit strong cationic selectivity
    Feliksas F Bukauskas
    Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
    J Membr Biol 245:243-53. 2012
  2. pmc Fast structural responses of gap junction membrane domains to AB5 toxins
    Irina V Majoul
    Institute of Biology, Center for Structural and Cell Biology in Medicine, University of Lubeck, 23562 Lübeck, Germany
    Proc Natl Acad Sci U S A 110:E4125-33. 2013
  3. doi The Connexin40A96S mutation from a patient with atrial fibrillation causes decreased atrial conduction velocities and sustained episodes of induced atrial fibrillation in mice
    Indra Lübkemeier
    Life and Medical Sciences LIMES Institute, Molecular Genetics, University of Bonn, Bonn, Germany
    J Mol Cell Cardiol 65:19-32. 2013
  4. pmc Deletion of the last five C-terminal amino acid residues of connexin43 leads to lethal ventricular arrhythmias in mice without affecting coupling via gap junction channels
    Indra Lübkemeier
    Life and Medical Sciences LIMES Institute, Molecular Genetics, University of Bonn, Carl Troll Str 31, 53115, Bonn, Germany
    Basic Res Cardiol 108:348. 2013
  5. pmc Intracellular magnesium-dependent modulation of gap junction channels formed by neuronal connexin36
    Nicolas Palacios-Prado
    Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    J Neurosci 33:4741-53. 2013
  6. pmc Regulation of connexin36 gap junction channels by n-alkanols and arachidonic acid
    Alina Marandykina
    Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    J Physiol 591:2087-101. 2013
  7. pmc Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury
    Nan Wang
    Faculty of Medicine and Health Sciences, Physiology Group, Department of Basic Medical Sciences, Ghent University, Ghent, Belgium
    Basic Res Cardiol 108:309. 2013
  8. pmc Connexin mimetic peptides inhibit Cx43 hemichannel opening triggered by voltage and intracellular Ca2+ elevation
    Nan Wang
    Physiology Group, Department of Basic Medical Sciences, Faculty of Medicine and Health Sciences, Ghent University, Belgium
    Basic Res Cardiol 107:304. 2012
  9. pmc Connexin and pannexin hemichannels in inflammatory responses of glia and neurons
    Michael V L Bennett
    Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    Brain Res 1487:3-15. 2012
  10. pmc Paracrine signaling through plasma membrane hemichannels
    Nan Wang
    Department of Basic Medical Sciences, Ghent University, Ghent, Belgium
    Biochim Biophys Acta 1828:35-50. 2013

Detail Information

Publications19

  1. pmc Neurons and β-cells of the pancreas express connexin36, forming gap junction channels that exhibit strong cationic selectivity
    Feliksas F Bukauskas
    Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
    J Membr Biol 245:243-53. 2012
    ..Thus, Cx36 GJs are highly cation-selective and should exhibit relatively low permeability to numerous vital negatively charged metabolites and high permeability to K⁺, a major charge carrier in cell-cell communication...
  2. pmc Fast structural responses of gap junction membrane domains to AB5 toxins
    Irina V Majoul
    Institute of Biology, Center for Structural and Cell Biology in Medicine, University of Lubeck, 23562 Lübeck, Germany
    Proc Natl Acad Sci U S A 110:E4125-33. 2013
    ..Our data demonstrate very fast dynamics (in the millisecond-to-second range) within GJ plaques, which previously were considered to be relatively stable, long-lived structures...
  3. doi The Connexin40A96S mutation from a patient with atrial fibrillation causes decreased atrial conduction velocities and sustained episodes of induced atrial fibrillation in mice
    Indra Lübkemeier
    Life and Medical Sciences LIMES Institute, Molecular Genetics, University of Bonn, Bonn, Germany
    J Mol Cell Cardiol 65:19-32. 2013
    ..We conclude that heterozygous Cx40A96S mice exhibit prolonged episodes of induced atrial fibrillation and severely reduced atrial conduction velocities similar to the corresponding human patient. ..
  4. pmc Deletion of the last five C-terminal amino acid residues of connexin43 leads to lethal ventricular arrhythmias in mice without affecting coupling via gap junction channels
    Indra Lübkemeier
    Life and Medical Sciences LIMES Institute, Molecular Genetics, University of Bonn, Carl Troll Str 31, 53115, Bonn, Germany
    Basic Res Cardiol 108:348. 2013
    ..The Cx43D378stop mice reveal for the first time that Cx43 dependent arrhythmias can develop by mechanisms other than impairment of gap junction channel function...
  5. pmc Intracellular magnesium-dependent modulation of gap junction channels formed by neuronal connexin36
    Nicolas Palacios-Prado
    Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    J Neurosci 33:4741-53. 2013
    ..Thus, this novel modulatory mechanism could underlie changes in neuronal synchronization under conditions in which ATP levels, and consequently [Mg(2+)]i, are modified...
  6. pmc Regulation of connexin36 gap junction channels by n-alkanols and arachidonic acid
    Alina Marandykina
    Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    J Physiol 591:2087-101. 2013
    ..In addition, SCCAs increase gj by interfering with endogenous AA-dependent inhibition, increasing open probability and the fraction of functional channels...
  7. pmc Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury
    Nan Wang
    Faculty of Medicine and Health Sciences, Physiology Group, Department of Basic Medical Sciences, Ghent University, Ghent, Belgium
    Basic Res Cardiol 108:309. 2013
    ..We conclude that preventing Cx43 hemichannel opening with Gap19 confers limited protective effects against myocardial ischemia/reperfusion injury...
  8. pmc Connexin mimetic peptides inhibit Cx43 hemichannel opening triggered by voltage and intracellular Ca2+ elevation
    Nan Wang
    Physiology Group, Department of Basic Medical Sciences, Faculty of Medicine and Health Sciences, Ghent University, Belgium
    Basic Res Cardiol 107:304. 2012
    ..Our results indicate that under pathological conditions, when [Ca(2+)](i) is elevated, Cx43 HC opening is promoted in cardiomyocytes and CxMPs counteract this effect...
  9. pmc Connexin and pannexin hemichannels in inflammatory responses of glia and neurons
    Michael V L Bennett
    Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    Brain Res 1487:3-15. 2012
    ..These studies implicate two kinds of gap junction hemichannel in inflammatory responses and cell death. This article is part of a Special Issue entitled Electrical Synapses...
  10. pmc Paracrine signaling through plasma membrane hemichannels
    Nan Wang
    Department of Basic Medical Sciences, Ghent University, Ghent, Belgium
    Biochim Biophys Acta 1828:35-50. 2013
    ..This article is part of a Special Issue entitled: The Communicating junctions, roles and dysfunctions...
  11. pmc Stochastic 16-state model of voltage gating of gap-junction channels enclosing fast and slow gates
    Nerijus Paulauskas
    Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, New York, USA
    Biophys J 102:2471-80. 2012
    ....
  12. pmc Modulation of metabolic communication through gap junction channels by transjunctional voltage; synergistic and antagonistic effects of gating and ionophoresis
    Nicolas Palacios-Prado
    Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA
    Biochim Biophys Acta 1818:1884-94. 2012
    ..This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics...
  13. pmc FGF-1 induces ATP release from spinal astrocytes in culture and opens pannexin and connexin hemichannels
    Juan M Garré
    Facultad de Medicina, Universidad de la República Oriental del Uruguay, C P 11800 Montevideo, Uruguay
    Proc Natl Acad Sci U S A 107:22659-64. 2010
    ..These changes in HCs and gap junction channels may promote inflammation and deprive neurons of astrocyte-mediated protection in spinal cord trauma and neurodegenerative disease...
  14. pmc Mouse lens connexin23 (Gje1) does not form functional gap junction channels but causes enhanced ATP release from HeLa cells
    Stephan Sonntag
    Institut fur Genetik, Abteilung Molekulargenetik, Universitat Bonn, D 53117 Bonn, Germany
    Eur J Cell Biol 88:65-77. 2009
    ..Therefore, Cx23 seems to share functional properties with pannexin (hemi) channels rather than gap junction channels of other connexins...
  15. pmc pH-dependent modulation of connexin-based gap junctional uncouplers
    Vytenis A Skeberdis
    Lithuanian University of Health Sciences, Institute of Cardiology, 17 Sukilėliųu Avenue, Kaunas 50009, Lithuania
    J Physiol 589:3495-506. 2011
    ..This suggests that LCCAs and some other uncouplers may act through the formation of hydrogen bonds with the as-of-yet unidentified histidine/s of the Cx45 GJ channel protein...
  16. pmc pH-dependent modulation of voltage gating in connexin45 homotypic and connexin45/connexin43 heterotypic gap junctions
    Nicolas Palacios-Prado
    Dominick P Purpura Department of Neuroscience and Department of Anesthesiology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    Proc Natl Acad Sci U S A 107:9897-902. 2010
    ..7, between the pK(a)s of Cx45 and Cx43-EGFP (approximately 6.5) homotypic GJs. In summary, pH(i) significantly modulates junctional conductance of Cx45 by affecting both V(j) gating and number of functional channels...
  17. pmc Heterotypic gap junction channels as voltage-sensitive valves for intercellular signaling
    Nicolas Palacios-Prado
    Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    Proc Natl Acad Sci U S A 106:14855-60. 2009
    ..This modulation of intercellular signaling by Vj can play a crucial role in many aspects of intercellular communication in the adult, in embryonic development, and in tissue regeneration...
  18. pmc A stochastic four-state model of contingent gating of gap junction channels containing two "fast" gates sensitive to transjunctional voltage
    Nerijus Paulauskas
    Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, The Bronx, New York, USA
    Biophys J 96:3936-48. 2009
    ..The proposed model can also be used to simulate gating properties of unapposed hemichannels...
  19. pmc Gating, permselectivity and pH-dependent modulation of channels formed by connexin57, a major connexin of horizontal cells in the mouse retina
    Nicolas Palacios-Prado
    Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    J Physiol 587:3251-69. 2009
    ....