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Reaction Diffusion Modeling of Calcium Dynamics with Realistic ER Geometry

Shawn Means ^*, Alexander J. Smith , Jason Shepherd ^*, John Shadid ^*, John Fowler ^*, Richard J. H. Wojcikiewicz , Tomas Mazel , Gregory D. Smith ^¶ and Bridget S. Wilson 

^* Sandia National Laboratory, Albuquerque, New Mexico; Department of Pathology and Cancer Research & Treatment Center, University of New Mexico School of Medicine, Albuquerque, New Mexico; Department of Pharmacology, SUNY Upstate Medical University, Syracuse, New York; and ^¶ Department of Applied Science, College of William and Mary, Williamsburg, Virginia

Correspondence: Address reprint requests to Bridget Wilson, Dept. of Pathology, Cancer Research Facility, Rm 205, University of New Mexico Health Sciences Center, Albuquerque, NM 87131. Tel.: 505-272-8852; E-mail: bwilson{at}salud.unm.edu.

We describe a finite-element model of mast cell calcium dynamics that incorporates the endoplasmic reticulum's complex geometry. The model is built upon a three-dimensional reconstruction of the endoplasmic reticulum (ER) from an electron tomographic tilt series. Tetrahedral meshes provide volumetric representations of the ER lumen, ER membrane, cytoplasm, and plasma membrane. The reaction-diffusion model simultaneously tracks changes in cytoplasmic and ER intraluminal calcium concentrations and includes luminal and cytoplasmic protein buffers. Transport fluxes via PMCA, SERCA, ER leakage, and Type II IP₃ receptors are also represented. Unique features of the model include stochastic behavior of IP₃ receptor calcium channels and comparisons of channel open times when diffusely distributed or aggregated in clusters on the ER surface. Simulations show that IP₃R channels in close proximity modulate activity of their neighbors through local Ca²⁺ feedback effects. Cytoplasmic calcium levels rise higher, and ER luminal calcium concentrations drop lower, after IP₃-mediated release from receptors in the diffuse configuration. Simulation results also suggest that the buffering capacity of the ER, and not restricted diffusion, is the predominant factor influencing average luminal calcium concentrations.

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