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 Ca(2+) in hepatocytes. Thanks to the development of imaging techniques, our understanding of the spatio-temporal organization of intracellular Ca(2+) 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 Ca(2+) from the endoplasmic reticulum. Besides the now well-known hepatic Ca(2+) oscillations induced by hormonal stimulation, intra- and intercellular Ca(2+) waves have also been observed. More recently, subcellular Ca(2+) increases associated with the coordinated opening of a few Ca(2+) 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 Ca(2+). Here, we review the various aspects of the spatio-temporal organization of cytosolic Ca(2+) in hepatocytes from the dual point of view provided by experiments and modeling. We first focus on the description and the mechanism of intracellular Ca(2+) oscillations and waves. Second, we investigate in which manner these repetitive Ca(2+) increases are coordinated among a set of hepatocytes coupled by gap junctions, a phenomenon known as 'intercellular Ca(2+) waves'. Finally, we focus on the so-called elementary Ca(2+) signals induced by low InsP(3) concentrations, leading to Ca(2+) 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 Ca(2+) rises that could also apply to hepatocytes.