Abstract : Calcium signaling results from a complex interplay between activation and inactivation of intracellular and extracellular calcium permeable channels. This complexity is obvious from the pattern of calcium signals observed with modest, physiological concentrations of calcium-mobilizing agonists, which typically present as sequential regenerative discharges of stored calcium, a process referred to as calcium oscillations. In this review, we discuss recent advances in understanding the underlying mechanism of calcium oscillations through the power of mathematical modeling. We also summarize recent findings on the role of calcium entry through store-operated channels in sustaining calcium oscillations and in the mechanism by which calcium oscillations couple to downstream effectors.
Abstract : In many cell types, specific and robust signalling relies on a high level of spatiotemporal organization of Ca2+ dynamics. In response to external stimulation, Ca2+ signals ranging from a small increase of a few tens of nanomolar concentrations at the mouth of an inositol 1, 4, 5-trisphosphate receptor to the periodic propagation of waves invading an organ or a tissue, can be observed. Here, we review our combined experimental and computational approach of Ca2+ dynamics, which has been mainly carried out on liver hepatocytes. We focus in particular on the understanding of the relationship between elementary Ca2+ increases, Ca2+ oscillations and intra- or intercellular Ca2+ waves. The physiological impact of such signalling on liver function is also discussed.
Abstract : Circadian clocks are regulated at the post-translational level by a variety of processes among which protein phosphorylation plays a prominent, though complex role. Thus, the phosphorylation of different sites on the clock protein PER by casein kinase CKI can lead to opposite effects on the stability of the protein and on the period of circadian oscillations. Here we extend a computational model previously proposed for the mammalian circadian clock by incorporating two distinct phosphorylations of PER by CKI. On the basis of experimental observations we consider that phosphorylation at one site (denoted here PER-P1) enhances the rate of degradation of the protein and decreases the period, while phosphorylation at another site (PER-P2) stabilizes the protein, enhances the transcription of the Per gene, and increases the period. The model also incorporates an additional phosphorylation of PER by the kinase GSK3. We show that the extended model incorporating the antagonistic effects of PER phosphorylations by CKI can account for observations pertaining to (i) the decrease in period in the Tau mutant, due to an increase in phosphorylation by CKI leading to PER-P1, and (ii) the Familial Advanced Sleep Phase Syndrome (FASPS) in which the period is shortened and the phase of the oscillations is advanced when the rate of phosphorylation leading to PER-P2 is decreased. The model further accounts for the increase in period observed in the presence of CKI inhibitors that decrease the rate of phosphorylation leading to both PER-P1 and PER-P2. A similar increase in period results from inhibition of GSK3.