Document Type
Article
Department/Program
Applied Science
Journal Title
Biophysical Journal
Pub Date
6-2014
Volume
106
Issue
12
First Page
2693
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.
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 [Oa(2+)] 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.
Recommended Citation
Weinberg, Seth H. and Smith, Gregory D., The Influence of Ca2+ Buffers on Free [Ca2+] Fluctuations and the Effective Volume of Ca2+ Microdomains (2014). Biophysical Journal, 106(12), 2693-2709.
https://doi.org/10.1016/j.bpj.2014.04.045
DOI
https://doi.org/10.1016/j.bpj.2014.04.045
