Functional Ca2+ Channels between Channel Clusters are Necessary for the Propagation of IP3R-Mediated Ca2+ Waves

Abstract

The specificity and universality of intracellular Ca 2 + signals rely on the variety of spatio-temporal patterns that the Ca 2 + concentration can display. Ca 2 + release into the cytosol through inositol 1,4,5-trisphosphate receptors (IP 3 Rs) is key for this variety. The opening probability of IP 3 Rs depends on the cytosolic Ca 2 + concentration. All of the dynamics are then well described by an excitable system in which the signal propagation depends on the ability of the Ca 2 + released through one IP 3 R to induce the opening of other IP 3 Rs. In most cell types, IP 3 Rs are organized in clusters, i.e., the cytosol is a “patchy” excitable system in which the signals can remain localized (i.e., involving the release through one or more IP 3 Rs in a cluster), or become global depending on the efficiency of the Ca 2 + -mediated coupling between clusters. The spatial range over which the signals propagate determines the responses that the cell eventually produces. This points to the importance of understanding the mechanisms that make the propagation possible. Our previous qualitative comparison between experiments and numerical simulations seemed to indicate that Ca 2 + release not only occurs within the close vicinity of the clearly identifiable release sites (IP 3 R clusters) but that there are also functional IP 3 Rs in between them. In this paper, we present a quantitative comparison between experiments and models that corroborate this preliminary conclusion. This result has implications on how the Ca 2 + -mediated coupling between clusters works and how it can eventually be disrupted by the different Ca 2 + trapping mechanisms.

High rates of calcium-free diffusion in the cytosol of living cells

“…It is the upper limit of the range of possible values, the free diffusion coefficient, that should remain fairly constant under various conditions. Knowing the range of possible values is relevant, especially for the understanding of situations in which the spatiotemporal distribution of intracellular Ca 2þ is a key aspect of the signaling, as in frequency-encoded responses (18), long distance coupling phenomena (19,20), or at the transition to propagating either intra- (21)(22)(23)(24) or inter- (25,26) cellular Ca 2þ waves. The direct quantification of the Ca 2þ diffusion coefficient and of how it varies through the interaction with buffers in living cells is therefore of utmost importance.…”