The Influence of Ca Buffers on Free [Ca] Fluctuations and the Effective Volume of Ca Microdomains |
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Authors: | Seth H Weinberg Gregory D Smith |
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Institution: | Department of Applied Science, The College of William & Mary, Williamsburg, Virginia |
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Abstract: | Intracellular calcium (Ca2+) plays a significant role in many cell signaling pathways, some of which are localized to spatially restricted microdomains. Ca2+ binding proteins (Ca2+ buffers) play an important role in regulating Ca2+ concentration (Ca2+]). Buffers typically slow Ca2+] temporal dynamics and increase the effective volume of Ca2+ domains. Because fluctuations in Ca2+] decrease in proportion to the square-root of a domain’s physical volume, one might conjecture that buffers decrease Ca2+] fluctuations and, consequently, mitigate the significance of small domain volume concerning Ca2+ signaling. We test this hypothesis through mathematical and computational analysis of idealized buffer-containing domains and their stochastic dynamics during free Ca2+ influx with passive exchange of both Ca2+ and buffer with bulk concentrations. We derive Langevin equations for the fluctuating dynamics of Ca2+ and buffer and use these stochastic differential equations to determine the magnitude of Ca2+] fluctuations for different buffer parameters (e.g., dissociation constant and concentration). In marked contrast to expectations based on a naive application of the principle of effective volume as employed in deterministic models of Ca2+ signaling, we find that mobile and rapid buffers typically increase the magnitude of domain Ca2+] fluctuations during periods of Ca2+ influx, whereas stationary (immobile) Ca2+ buffers do not. Also contrary to expectations, we find that in the absence of Ca2+ influx, buffers influence the temporal characteristics, but not the magnitude, of Ca2+] fluctuations. We derive an analytical formula describing the influence of rapid Ca2+ buffers on Ca2+] fluctuations and, importantly, identify the stochastic analog of (deterministic) effective domain volume. Our results demonstrate that Ca2+ buffers alter the dynamics of Ca2+] fluctuations in a nonintuitive manner. The finding that Ca2+ buffers do not suppress intrinsic domain Ca2+] fluctuations raises the intriguing question of whether or not Ca2+] fluctuations are a physiologically significant aspect of local Ca2+ signaling. |
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