Responses of Ca2+-binding proteins to localized, transient changes in intracellular [Ca2+]

In smooth muscle cells, various transient, localized [Ca(2+)] changes have been observed that are thought to regulate cell function without necessarily inducing contraction. Although a great deal of effort has been put into detecting these transients and elucidating the mechanisms involved in their generation, the extent to which these transient Ca(2+) signals interact with intracellular Ca(2+)-binding molecules remains relatively unknown. To understand how the spatial and temporal characteristics of an intracellular Ca(2+) signal influence its interaction with Ca(2+)-binding proteins, mathematical models of Ca(2+) diffusion and regulation in smooth muscle cells were used to study Ca(2+) binding to prototypical proteins with one or two Ca(2+)-binding sites. Simulations with the models: (1) demonstrate the extent to which the rate constants for Ca(2+)-binding to proteins and the spatial and temporal characteristics of different Ca(2+) transients influence the magnitude and time course of the responses of these proteins to the transients; (2) predict significant differences in the responses of proteins with one or two Ca(2+)-binding sites to individual Ca(2+) transients and to trains of transients; (3) demonstrate how the kinetic characteristics determine the fidelity with which the responses of Ca(2+)-sensitive molecules reflect the magnitude and time course of transient Ca(2+) signals. Overall, this work demonstrates the clear need for complete information about the kinetics of Ca(2+) binding for determining how well Ca(2+)-binding molecules respond to different types of Ca(2+) signals. These results have important implications when considering the possible modulation of Ca(2+)- and Ca(2+)/calmodulin-dependent proteins by localized intracellular Ca(2+) transients in smooth muscle cells and, more generally, in other cell types.