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Cytosolic Ca²⁺ Buffers Are Inherently Ca²⁺ Signal Modulators.

ABSTRACT: For precisely regulating intracellular Ca²⁺ signals in a time- and space-dependent manner, cells make use of various components of the "Ca²⁺ signaling toolkit," including Ca²⁺ entry and Ca²⁺ extrusion systems. A class of cytosolic Ca²⁺-binding proteins termed Ca²⁺ buffers serves as modulators of such, mostly short-lived Ca²⁺ signals. Prototypical Ca²⁺ buffers include parvalbumins (α and β isoforms), calbindin-D9k, calbindin-D28k, and calretinin. Although initially considered to function as pure Ca²⁺ buffers, that is, as intracellular Ca²⁺ signal modulators controlling the shape (amplitude, decay, spread) of Ca²⁺ signals, evidence has accumulated that calbindin-D28k and calretinin have additional Ca²⁺ sensor functions. These other functions are brought about by direct interactions with target proteins, thereby modulating their targets' function/activity. Dysregulation of Ca²⁺ buffer expression is associated with several neurologic/neurodevelopmental disorders including autism spectrum disorder (ASD) and schizophrenia. In some cases, the presence of these proteins is presumed to confer a neuroprotective effect, as evidenced in animal models of Parkinson's or Alzheimer's disease.

SUBMITTER: Schwaller B

PROVIDER: S-EPMC6942125 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Intracellular calcium (Ca(2+)) plays a significant role in many cell signaling pathways, some of which are localized to spatially restricted microdomains. Ca(2+) binding proteins (Ca(2+) buffers) play an important role in regulating Ca(2+) concentration ([Ca(2+)]). Buffers typically slow [Ca(2+)] temporal dynamics and increase the effective volume of Ca(2+) domains. Because fluctuations in [Ca(2+)] decrease in proportion to the square-root of a domain's physical volume, one might conjecture that buffers decrease [Ca(2+)] fluctuations and, consequently, mitigate the significance of small domain volume concerning Ca(2+) signaling. We test this hypothesis through mathematical and computational analysis of idealized buffer-containing domains and their stochastic dynamics during free Ca(2+) influx with passive exchange of both Ca(2+) and buffer with bulk concentrations. We derive Langevin equations for the fluctuating dynamics of Ca(2+) and buffer and use these stochastic differential equations to determine the magnitude of [Ca(2+)] 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 Ca(2+) signaling, we find that mobile and rapid buffers typically increase the magnitude of domain [Ca(2+)] fluctuations during periods of Ca(2+) influx, whereas stationary (immobile) Ca(2+) buffers do not. Also contrary to expectations, we find that in the absence of Ca(2+) influx, buffers influence the temporal characteristics, but not the magnitude, of [Ca(2+)] fluctuations. We derive an analytical formula describing the influence of rapid Ca(2+) buffers on [Ca(2+)] fluctuations and, importantly, identify the stochastic analog of (deterministic) effective domain volume. Our results demonstrate that Ca(2+) buffers alter the dynamics of [Ca(2+)] fluctuations in a nonintuitive manner. The finding that Ca(2+) buffers do not suppress intrinsic domain [Ca(2+)] fluctuations raises the intriguing question of whether or not [Ca(2+)] fluctuations are a physiologically significant aspect of local Ca(2+) signaling.

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Cytosolic Ca2+ Buffers Are Inherently Ca2+ Signal Modulators.

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Cytosolic Ca²⁺ Buffers Are Inherently Ca²⁺ Signal Modulators.