Coordinated intercellular calcium waves induced by noradrenaline in rat hepatocytes: dual control by gap junction permeability and agonist.
Calcium-mobilizing agonists induce intracellular Ca2+ concentration ([Ca2+]i) changes thought to trigger cellular responses. In connected cells, rises in [Ca2+]i can propagate from cell to cell as intercellular Ca2+ waves, the mechanisms of which are not elucidated. Using fura2-loaded rat hepatocytes, we studied the mechanisms controlling coordination and intercellular propagation of noradrenaline-induced Ca2+ signals. Gap junction blockade with 18 alpha-glycyrrhetinic acid resulted in a loss of coordination between connected cells. We found that second messengers and [Ca2+]i rises in one hepatocyte cannot trigger Ca2+ responses in connected cells, suggesting that diffusion across gap junctions, while required for coordination, is not sufficient by itself for the propagation of intercellular Ca2+ waves. In addition, our experiments revealed functional differences between noradrenaline-induced Ca2+ signals in connected hepatocytes. These results demonstrate that intercellular Ca2+ signals in multicellular systems of rat hepatocytes are propagated and highly organized through complex mechanisms involving at least three factors. First, gap junction coupling ensures coordination of [Ca2+]i oscillations between the different cells; second, the presence of hormone at each hepatocyte is required for cell-cell Ca2+ signal propagation; and third, functional differences between adjacent connected hepatocytes could allow a 'pacemaker-like' intercellular spread of Ca2+ waves.
Tordjmann
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T
Unité de Recherche U.442, Institut National de la Santé et de la Recherche Médicale, Université Paris Sud, IFR-FR 46, Bat. 443, 91405 Orsay, France.
Berthon
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B
Claret
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M
Combettes
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D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002450:Cell Communication; D002463:Cell Membrane Permeability / Q000187:drug effects; D004058:Diffusion; D005260:Female; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism*; D006034:Glycyrrhetinic Acid / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology*; D019899:Paracrine Communication; D010477:Perfusion; D010507:Periodicity; D051381:Rats; D017208:Rats, Wistar
D006034:Glycyrrhetinic Acid; D002118:Calcium; D009638:Norepinephrine