Nicolas Le Novère
Speaker of Workshop 2
Will talk about: Relative activation of calcineurin and CaMKII by frequency, duration and amplitude of calcium signals
The research interests of Le Novère revolve around the modelling of signal transduction in neurons, ranging from the molecular structure of proteins involved in neurotransmission, to signalling pathways in relation with synaptic plasticity. Using different modelling approaches at different levels, his group provided new insights on mechanisms leading to cooperativity, integration, and decoding of intracellular signals. Along with the modelling activity, the group develops services for the community such as data resources or modelling software. Le Novère is one of the creators of the Systems Biology Markup Language (SBML), and has been involved in it development since 2000. Along with the tools and resources developed for computational systems biology (e.g., BioModels Database, the reference for exchanging models), Le Novère initiated a coherent set of standards and ontologies in systems biology modeling, such as the Minimum Information Required In the Annotation of Models (MIRIAM), the Minimum Information About a Simulation Experiment (MIASE), the Simulation Experiment Description Markup Language (SED-ML) and the Systems Biology Ontology (SBO), that together aim to facilitate the exchange and reuse of models, as well as their integration with other types of biological data. Over the last few years, he coordinated the development of the Systems Biology Graphical Notation (SBGN), the equivalent for biochemistry of the circuit diagrams for engineering.
Both long-term potentiation (LTP) and long-term depression (LTD) are modulated 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\textsuperscript{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 towards 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.
