Coordinated intercellular calcium waves induced by noradrenaline in rat hepatocytes: dual control by gap junction permeability and agonist

• Published in: The EMBO journal 1997-09, Vol.16 (17), p.5398-5407
• Main Authors: Tordjmann, Thierry, Berthon, Brigitte, Claret, Michel, Combettes, Laurent
• Format: Article
• Language: English
• Subjects: Animals; Ca2+ waves; Calcium - metabolism; Cell Communication; Cell Membrane Permeability - drug effects; Diffusion; Female; gap junction; Gap Junctions - drug effects; Gap Junctions - metabolism; Glycyrrhetinic Acid - pharmacology; hepatocytes; intercellular; Liver - cytology; Liver - drug effects; Liver - metabolism; Norepinephrine - pharmacology; Paracrine Communication; Perfusion; Periodicity; Rats; Rats, Wistar
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/16.17.5398

Calcium‐mobilizing agonists induce intracellular Ca 2+ concentration ([Ca 2+ ] i ) changes thought to trigger cellular responses. In connected cells, rises in [Ca 2+ ] i can propagate from cell to cell as intercellular Ca 2+ 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 Ca 2+ signals. Gap junction blockade with 18 α‐glycyrrhetinic acid resulted in a loss of coordination between connected cells. We found that second messengers and [Ca 2+ ] i rises in one hepatocyte cannot trigger Ca 2+ responses in connected cells, suggesting that diffusion across gap junctions, while required for coordination, is not sufficient by itself for the propagation of intercellular Ca 2+ waves. In addition, our experiments revealed functional differences between noradrenaline‐induced Ca 2+ signals in connected hepatocytes. These results demonstrate that intercellular Ca 2+ 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 [Ca 2+ ] i oscillations between the different cells; second, the presence of hormone at each hepatocyte is required for cell‐cell Ca 2+ signal propagation; and third, functional differences between adjacent connected hepatocytes could allow a ‘pacemaker‐like’ intercellular spread of Ca 2+ waves.