Hierarchical organization of calcium signals in hepatocytes: from experiments to models

The proper working of the liver largely depends on the fine tuning of the level of cytosolic Ca2+ in hepatocytes. Thanks to the development of imaging techniques, our understanding of the spatio-temporal organization of intracellular Ca2+ in this - and other - cell types has much improved. Many of these signals are mediated by a rise in the level of inositol 1,4,5-trisphosphate (InsP(3)), a second messenger which can activate the release of Ca2+ from the endoplasmic reticulum. Besides the now well-known hepatic Ca2+ oscillations induced by hormonal stimulation, intra- and intercellular Ca2+ waves have also been observed. More recently, subcellular Ca2+ increases associated with the coordinated opening of a few Ca2+ channels have been reported. Given the complexity of the regulations involved in the generation of such processes and the variety of time and length scales necessary to describe those phenomena, theoretical models have been largely used to gain a precise and quantitative understanding of the dynamics of intracellular Ca2+. Here, we review the various aspects of the spatio-temporal organization of cytosolic Ca2+ in hepatocytes from the dual point of view provided by experiments and modeling. We first focus on the description and the mechanism of intracellular Ca2+ oscillations and waves. Second, we investigate in which manner these repetitive Ca2+ increases are coordinated among a set of hepatocytes coupled by gap junctions, a phenomenon known as 'intercellular Ca2+ waves'. Finally, we focus on the so-called elementary Ca2+ signals induced by low InsP(3) concentrations, leading to Ca2+ rises having a spatial extent of a few microns. Although these small-scale events have been mainly studied in other cell types, we theoretically infer general properties of these localized intracellular Ca2+ rises that could also apply to hepatocytes. (C) 2000 Elsevier Science B.V. All rights reserved.