Biophysical attributes that affect CaMKII activation deduced with a novel spatial stochastic simulation approach

Area of Science:

• Neuroscience
• Biochemistry
• Computational Biology

Background:

• Calcium/calmodulin-dependent protein kinase II (CaMKII) holoenzymes are crucial for neuronal Ca2+ signal decoding.
• Simulating CaMKII detailed kinetics is challenging due to its multi-subunit structure, leading to combinatorial complexity.

Purpose of the Study:

• To develop a novel computational method for detailed simulation of the Ca2+-calmodulin-CaMKII reaction network, incorporating diffusion and managing combinatorial complexity.
• To investigate how Ca2+ signal frequency, calmodulin availability, and Ca2+ diffusion rates affect CaMKII activation patterns.

Main Methods:

• Customization of the stochastic particle-based simulator Smoldyn to handle the combinatorial explosion of CaMKII species.
• Simulation of CaMKII activation by Ca2+-loaded calmodulin under varying Ca2+ input conditions, considering spatial and temporal dynamics.

Main Results:

• CaMKII phosphorylation dependence on Ca2+ signal frequency is inherent to network kinetics.
• Activation patterns are modulated by Ca2+/calmodulin ratios, Ca2+ diffusion rates, and Ca2+ influx saturation.
• Holoenzyme structure subtly influences CaMKII activation, with more extended subunits facilitating calmodulin access.

Conclusions:

• Intracellular factors like crowding and calmodulin availability significantly impact Ca2+ signal decoding by CaMKII.
• Distinct CaMKII activation patterns arise in different cellular compartments (dendritic spines, nanodomains, cytoplasm) due to these factors.