Calcium input frequency, duration and amplitude differentially modulate the relative activation of calcineurin and CaMKII

• Published in: PloS one 2012-09, Vol.7 (9), p.e43810-e43810
• Main Authors: Li, Lu, Stefan, Melanie I, Le Novère, Nicolas
• Format: Article
• Language: English
• Subjects: Activation; Animals; Biochemistry; Bioinformatics; Biology; Ca2+/calmodulin-dependent protein kinase II; Calcineurin; Calcineurin - physiology; Calcium; Calcium - metabolism; Calcium - pharmacology; Calcium ions; Calcium Signaling; Calcium signalling; Calcium-binding protein; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - physiology; Calmodulin; Computer applications; Computer Simulation; Enzyme Activation; Glutamic acid receptors (ionotropic); High frequencies; Hippocampus - cytology; Hippocampus - drug effects; Hippocampus - physiology; Humans; Kinases; Long-term depression; Long-term potentiation; Medicine; Models, Molecular; N-Methyl-D-aspartic acid receptors; Neuronal Plasticity; Neurons - cytology; Neurons - drug effects; Neurons - physiology; Phosphatase; Phosphatases; Proteins; Receptors, N-Methyl-D-Aspartate - physiology; Regulation; Rodents; Synaptic plasticity; Synaptic Transmission
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0043810

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 Ca(2+)/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.