title: Connexin43 hemichannel-mediated regulation of connexin43.
abstract: BACKGROUND
  Many signaling molecules and pathways that regulate gap junctions (GJs) protein expression and function are, in fact, also controlled by GJs. We, therefore, speculated an existence of the GJ channel-mediated self-regulation of GJs. Using a cell culture model in which nonjunctional connexin43 (Cx43) hemichannels were activated by cadmium (Cd(2+)), we tested this hypothesis.
  
  
  RESULTS
  Incubation of Cx43-transfected LLC-PK1 cells with Cd(2+) led to an increased expression of Cx43. This effect of Cd(2+) was tightly associated with JNK activation. Inhibition of JNK abolished the elevation of Cx43. Further analysis revealed that the changes of JNK and Cx43 were controlled by GSH. Supplement of a membrane-permeable GSH analogue GSH ethyl ester or GSH precursor N-acetyl-cystein abrogated the effects of Cd(2+) on JNK activation and Cx43 expression. Indeed, Cd(2+) induced extracellular release of GSH. Blockade of Cx43 hemichannels with heptanol or Cx43 mimetic peptide Gap26 to prevent the efflux of GSH significantly attenuated the Cx43-elevating effects of Cd(2+).
  
  
  CONCLUSIONS
  Collectively, our results thus indicate that Cd(2+)-induced upregulation of Cx43 is through activation of nonjunctional Cx43 hemichannels. Our findings thus support the existence of a hemichannel-mediated self-regulation of Cx43 and provide novel insights into the molecular mechanisms of Cx43 expression and function.
authors: Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan. cmu_likai@hotmail.com
authors: Kai
authors: K
authors: Li
authors: Yuan
authors: Y
authors: Chi
authors: Kun
authors: K
authors: Gao
authors: Qiaojing
authors: Q
authors: Yan
authors: Hiroyuki
authors: H
authors: Matsue
authors: Masayuki
authors: M
authors: Takeda
authors: Masanori
authors: M
authors: Kitamura
authors: Jian
authors: J
authors: Yao
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002104:Cadmium / Q000494:pharmacology; D018031:Connexin 43 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D018374:LLC-PK1 Cells; D008954:Models, Biological; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D013552:Swine; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018031:Connexin 43; C514423:Gap 26 peptide; D010455:Peptides; D016755:Proto-Oncogene Proteins c-jun; D002104:Cadmium; D000255:Adenosine Triphosphate; D048031:JNK Mitogen-Activated Protein Kinases; D005978:Glutathione