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Mechanism of receptor-oriented intercellular calcium wave propagation in hepatocytes

GENEVIÈVE DUPONT^*, THIERRY TORDJMANN, CAROLINE CLAIR, STÉPHANE SWILLENS, MICHEL CLARET and LAURENT COMBETTES¹

^* Université Libre de Bruxelles, Faculté des Sciences CP231, Brussels, Belgium;
Unité de Recherche U442, Institut National de la Santé et de la Recherche Médicale, Université de Paris sud, Orsay, France; and
Université Libre de Bruxelles, IRIBHN, Faculté de Médecine, Campus Erasme, Brussels, Belgium

¹Correspondence: Unité de Recherche U442, Institut National de la Santé et de la Recherche Médicale, Université de Paris sud, bâ 443, 91405 Orsay, France. E-mail: laurent.combettes{at}ibaic.u-psud.fr

Intercellular calcium signals are propagated in multicellular hepatocyte systems as well as in the intact liver. The stimulation of connected hepatocytes by glycogenolytic agonists induces reproducible sequences of intracellular calcium concentration increases, resulting in unidirectional intercellular calcium waves. Hepatocytes are characterized by a gradient of vasopressin binding sites from the periportal to perivenous areas of the cell plate in hepatic lobules. Also, coordination of calcium signals between neighboring cells requires the presence of the agonist at each cell surface as well as gap junction permeability. We present a model based on the junctional coupling of several hepatocytes differing in sensitivity to the agonist and thus in the intrinsic period of calcium oscillations. In this model, each hepatocyte displays repetitive calcium spikes with a slight phase shift with respect to neighboring cells, giving rise to a phase wave. The orientation of the apparent calcium wave is imposed by the direction of the gradient of hormonal sensitivity. Calcium spikes are coordinated by the diffusion across junctions of small amounts of inositol 1,4,5-trisphosphate (InsP₃). Theoretical predictions from this model are confirmed experimentally. Thus, major physiological insights may be gained from this model for coordination and spatial orientation of intercellular signals.—Dupont, G., Tordjmann, T., Clair, C., Swillens, S., Claret, M., Combettes, L. Mechanism of receptor-oriented intercellular calcium wave propagation in hepatocytes.

Key Words: liver • phase wave • gap junctions • inositol 1,4,5-trisphosphate

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