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bioRxiv · 10.64898/2026.02.11.705296

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

Jedrzejewska-Szmek, J.·Blackwell, K. T.
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Abstract

Calcium dynamics controls learning and memory, and abnormal calcium dynamics have been implicated in neurodegenerative disorders, such as Alzheimers 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 [1] 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 {beta}-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. Author summaryCalcium dynamics controls learning and memory. In neurons calcium dynamics are regulated by a complex system including calcium-permeable channels and extrusion pumps. The components of this system are regulated by calmodulin, which is enriched in the brain. We show that relieving calmodulin inhibition of calcium permeable channels, which accompanies aging, decreases spatial and temporal specificity of calcium release, contributing to the deficits in learning and memory observed in old age. In contrast, calcium extrusion pumps that are activated by calmodulin are likely responsible for increased resting intracellular calcium concentration observed in Alzheimers disease. In consequence, a novel role emerges for calmodulin, which in the brain is primarily considered a fast-acting calcium buffering molecule, as an important regulator in neuronal calcium dynamics underlying pathology.

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Jedrzejewska-Szmek, J., Blackwell, K. T.. 2026-02-13. Calmodulin controls spatial and temporal specificity of calcium-induced calcium release. https://doi.org/10.64898/2026.02.11.705296

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