Connexin43 Hemichannel-Mediated Regulation of Connexin43

• DOI: 10.1371/journal.pone.0058057
• Publication Date: 2013-02-27T22:51:03Z
• Authors: Kai Li; Yuan Chi; Kun Gao; Qiaojing Yan; Hiroyuki Matsue; Masayuki Takeda; Masanori Kitamura; Jian Yao
• Keywords: Proto-Oncogene Proteins c-jun; Swine; Science; Models, Biological; 03 medical and health sciences; Adenosine Triphosphate; Animals; Humans; Phosphorylation; 0303 health sciences; Q; R; JNK Mitogen-Activated Protein Kinases; Gap Junctions; Glutathione; Rats; Up-Regulation; Enzyme Activation; Protein Transport; Connexin 43; Medicine; LLC-PK1 Cells; Peptides; Research Article; Cadmium

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.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+).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.