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 l evel of cytosolic Ca2+ in hepatocytes. Thanks to the development of imaging techniques, our understanding of the spatio-temporal organization of intra cellular Ca2+ in this - and other - cell types has much improved. Many of t hese signals are mediated by a rise in the level of inositol 1,4,5-trisphos phate (InsP(3)), a second messenger which can activate the release of Ca2from the endoplasmic reticulum. Besides the now well-known hepatic Ca2+ osc illations induced by hormonal stimulation, intra- and intercellular Ca2+ wa ves have also been observed. More recently, subcellular Ca2+ increases asso ciated with the coordinated opening of a few Ca2+ channels have been report ed. Given the complexity of the regulations involved in the generation of s uch processes and the variety of time and length scales necessary to descri be those phenomena, theoretical models have been largely used to gain a pre cise 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 exper iments 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 hepa tocytes 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 exte nt of a few microns. Although these small-scale events have been mainly stu died in other cell types, we theoretically infer general properties of thes e localized intracellular Ca2+ rises that could also apply to hepatocytes. (C) 2000 Elsevier Science B.V. All rights reserved.