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Published September 4, 2012 | Published + Supplemental Material
Journal Article Open

Calcium Input Frequency, Duration and Amplitude Differentially Modulate the Relative Activation of Calcineurin and CaMKII

Abstract

NMDA receptor dependent long-term potentiation (LTP) and long-term depression (LTD) are two prominent forms of synaptic plasticity, both of which are triggered by post-synaptic calcium elevation. To understand how calcium selectively stimulates two opposing processes, we developed a detailed computational model and performed simulations with different calcium input frequencies, amplitudes, and durations. We show that with a total amount of calcium ions kept constant, high frequencies of calcium pulses stimulate calmodulin more efficiently. Calcium input activates both calcineurin and Ca2+/calmodulin-dependent protein kinase II (CaMKII) at all frequencies, but increased frequencies shift the relative activation from calcineurin to CaMKII. Irrespective of amplitude and duration of the inputs, the total amount of calcium ions injected adjusts the sensitivity of the system to calcium input frequencies. At a given frequency, the quantity of CaMKII activated is proportional to the total amount of calcium. Thus, an input of a small amount of calcium at high frequencies can induce the same activation of CaMKII as a larger amount, at lower frequencies. Finally, the extent of activation of CaMKII signals with high calcium frequency is further controlled by other factors, including the availability of calmodulin, and by the potency of phosphatase inhibitors.

Additional Information

© 2012 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received March 4, 2012; Accepted July 26, 2012; Published September 4, 2012. Editor: Zhong-Ping Feng, University of Toronto, Canada. Funding: These authors have no support or funding to report. Competing Interests: The authors have declared that no competing interests exist. We thank Stuart J. Edelstein and Massimo Lai for helpful suggestions during the modelling work, and the E-Cell team for providing technical support. Author Contributions: Conceived and designed the experiments: LL MIS NL. Performed the experiments: LL. Analyzed the data: LL. Contributed reagents/materials/ analysis tools: LL MIS. Wrote the paper: LL MIS NL.

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August 19, 2023
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