Calmodulin controls spatial and temporal specificity of calcium-induced calcium release.

Overview

1. Nencki Institute of Experimental Biology Polish Academy of Sciences, Warszawa, Poland
2. Roy J. Carver Department of Biomedical Engineering and Iowa Neuroscience Institute, University of Iowa, Iowa City, Iowa, United States of America

Abstract

Calcium dynamics controls learning and memory, and abnormal calcium dynamics have been implicated in neurodegenerative disorders, such as Alzheimer’s disease (AD). Calcium dynamics are influenced by calcium-induced calcium release (CICR), which is mediated by ryanodine receptors (RyR) located on endoplasmic reticulum (ER) membrane. Calmodulin, one of the most abundant proteins in the brain, inhibits RyR2, expressed in the dendrites of hippocampal CA1 neurons, with several reported consequences: relief of this inhibition is responsible for heart failure, and enhancing calmodulin to RyR binding alleviates cell loss and AD-like neuronal hyperexcitability. To investigate the role of calmodulin in aging and AD, we built a sophisticated reaction-diffusion model of a dendritic branch with ER. We showed that relieving calmodulin inhibition of RyR2 increased spatial and temporal spread of calcium transients in the dendrite. This effect was also visible in a model of old age, where disinhibition of half of the RyR2 population increased spatial spread of calcium transients by a factor of 2, and disinhibition of RyR2 combined with increased concentration of calcium buffering molecules increased duration of calcium transients. Lower activation of plasma membrane calcium ATPase (PMCA), which is also activated by calmodulin and inhibited by β-Amyloid oligomers, and not RyR2 disinhibition, led to an increase in resting intracellular calcium concentration as observed in AD. Overall, our research demonstrates that changes in calmodulin that are associated with AD and aging, by regulation of RyR2 (in old age) and PMCA (in AD), underlie changes in calcium dynamics that might have consequences for learning and memory.

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Code is available at https://github.com/asiaszmek/stochastic_ER.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 2 authors, 14 MeSH terms, 117 references.

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This paper

Jędrzejewska-Szmek, J., & Blackwell, K. T. (2026). Calmodulin controls spatial and temporal specificity of calcium-induced calcium release. PLoS computational biology, 22(9), e1013752. https://doi.org/10.1371/journal.pcbi.1013752

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