Modelling the spatio-temporal organization of the agonist-induced intracellular calcium signals

Dupont, G.

Université Libre de Bruxelles, Faculté de Sciences, CP231, B-1050 Brussels, Belgium

Intracellular Ca²⁺ oscillations represent a prototype of rhythmic phenomenon at the cellular level. They have been observed in many different cell types such as hepatocytes, oocytes, myocytes, endothelial, pancreatic or glial cells. These oscillations -whose period can vary from less than one second to some thirty minutes- occur through periodic Ca²⁺ exchanges between the cytosol and the intracellar Ca²⁺ stores (endo- or sarcoplasmic reticulum). Release from the latter stores is initiated by an hormone-induced rise in inositol 1,4,5-trisphosphate (InsP3) and is then amplified by cytosolic Ca²⁺ itself, through the so-called Ca²⁺-induced Ca²⁺ release (CICR) regulation. Models based on this autocatalytic mechanism can account for the existence and the main properties of these oscillations.
Cytosolic Ca²⁺ oscillations also occur at fertilization in mammals, just after sperm binding. Experiments performed by artificially activating the eggs clearly show that the pulsatile nature of the Ca²⁺ signal plays an important role in relieving the egg from its metaphase arrest. Such a problem is now thought to have important implications in the field of in vitro fertilization. The Ca²⁺-calmodulin dependant kinase II (CaMKII) is the mediator between Ca²⁺ increases and the activation of the cell cycle machinery. A model based on the existence of two pathways between CaMKII and the cell cycle oscillator provide a link between these 2 fundamental oscillators, and is able to account for many experimental observations.
Besides the temporal organization, intracellular Ca²⁺ signalling is also characterized by a high level of spatial organization. The initially localized Ca²⁺ increase indeed propagates through the whole cell as a wave front, with velocities ranging from ten to hundred microns per second, depending on the cell type. These Ca²⁺ waves can be simulated when considering cytosolic Ca²⁺ diffusion in the model initially developed for Ca²⁺ oscillations. Numerical simulations thus allow to investigate the properties of these waves and to predict their behaviour when altering physiologically relevant parameters.

LOCATION	DATE	TIME
Lecture Hall II	Thursday, April 9	08:30 am