title: The metabolic inhibitor antimycin A can disrupt cell-to-cell communication by an ATP- and Ca(2+)-independent mechanism.
abstract: In cardiac myocytes of new-born rats, the degree of intercellular communication through gap junctional channels closely depends on the metabolic state of the cells. In contrast, in stably transfected HeLa cells expressing rat cardiac connexin43 (Cx43, the main channel-forming protein present in ventricular myocytes), a major part of junctional communication persisted in ATP-depleted conditions, in the presence of a metabolic inhibitor (KCN) or of a broad spectrum inhibitor of protein kinases (H7). However, another metabolic inhibitor, antimycin A, which like cyanide inhibits electron transfer in the respiratory chain, totally interrupted cell-to-cell communication between Cx43-HeLa cells, even in whole-cell conditions, when ATP (5 mM) was present. Antimycin A caused a modest increase in cytosolic calcium concentration; however, junctional uncoupling still occurred when this rise was prevented. Conditions of ischemic insult (e.g. ischemia or chemical hypoxia) frequently cause the activation of protein kinases, particularly of Src and MAP kinases, and such activations are known to markedly disrupt gap junctional communication. Antimycin-induced junctional uncoupling occurred even in the presence of inhibitors of these kinases. Antimycin A appears able to cause junctional uncoupling either through the ATP depletion it induces as a metabolic poison or via a direct action on gap junction constituents.
mesh_terms: D000255:Adenosine Triphosphate / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D000968:Antimycin A / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D002450:Cell Communication / Q000187:drug effects*; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells / Q000378:metabolism / Q000502:physiology; D019850:Heptanol / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000502:physiology*; D009994:Osmolar Concentration; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D011190:Potassium Cyanide / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000963:Antimetabolites; D018031:Connexin 43; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D000968:Antimycin A; D019850:Heptanol; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D011190:Potassium Cyanide; D002118:Calcium