Schedule Sep 02, 2003
Regulation of Intercellular Calcium Waves - Predictions of Mathematical Models
Dr. Thomas Höfer, Humboldt-Universität, Berlin

Calcium waves serve as a pathway of intercellular signalling in such diverse systems as the liver and the astrocyte networks of the nervous system. Various schemes for intercellular waves have been proposed, in which wave propagation relies on the diffusion of messengers through gap junctions or across the extracellular space, or both. The schemes differ with respect to the messenger species exchanged and the role of feedback mechanisms that can regenerate the propagating signal. We have studied intercellular wave propagation in a simple reaction-diffusion model accounting for regenerative calcium release and gap-junctional diffusion of calcium or IP3. The analysis shows that the types of signals that can be obtained depend on the diffusivity of the messenger carrying intercellular propagation. If propagation proceeds by calcium-induced calcium release and calcium diffusion, one can find either travelling waves or localized signals that fail to propagate beyond a stimulated cell or its immediate neighbourhood. If propagation relies on the more readily diffusible IP3, one additionally obtains signals with a long yet finite range of propagation. Based on data recorded in rat striatal astrocytes, we developed and analysed a more detailed model of intercellular calcium signalling in astrocyte networks. The kinetic equations account for IP3 generation, including its activation by cytoplasmic calcium, IP3-induced calcium liberation from intracellular stores and various other calcium transports, and both cytoplasmic and gap-junctional diffusion of IP3 and calcium ions. Rate constants for calcium release and sequestration were estimated from experimental data; the kinetic parameters for calcium-activated IP3 production and intercellular IP3 diffusion were taken as control parameters in the analysis of the model. Depending on their values, we find the three types of signals predicted by the simple model: localised diffusive signals, limited regenerative signals, and fully regenerative waves. The gap-junctional permeability for IP3 is the crucial permissive factor for signal propagation, and heterogeneity of gap-junctional coupling yields preferential pathways of propagation. Processes involved in both signal initiation (IP3 production activated by neurotransmitter) and regeneration (activation of IP3 production by calcium, loading of the calcium stores) exert the main control on the signalling range. The refractory period of signalling strongly depends on the refilling kinetics of the calcium stores. Thus the model identifies multiple steps that may be involved in the regulation of this intercellular signalling pathway.
Christian Giaume and Laurent Venance (Collège de France) are gratefully acknowledged for stimulating collaboration.

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