Reaction diffusion modeling of calcium dynamics with realistic ER geometry.

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.

[1]  S. Lowen.  The Biophysical Journal , 1960, Nature.

[2]  G. Warren,et al.  Density of newly synthesized plasma membrane proteins in intracellular membranes. I. Stereological studies , 1984, The Journal of cell biology.

[3]  J. Moore,et al.  The mechanism of the calcium signal and correlation with histamine release in 2H3 cells. , 1984, The Journal of biological chemistry.

[4]  G. Warren,et al.  Density of newly synthesized plasma membrane proteins in intracellular membranes II. Biochemical studies , 1984, The Journal of cell biology.

[5]  D. Tillotson,et al.  The rate of diffusion of Ca2+ and Ba2+ in a nerve cell body. , 1985, Biophysical journal.

[6]  G. G. Deanin,et al.  Membrane and cytoskeletal changes associated with IgE-mediated serotonin release from rat basophilic leukemia cells , 1985, The Journal of cell biology.

[7]  R. Huganir,et al.  Purified inositol 1,4,5-trisphosphate receptor mediates calcium flux in reconstituted lipid vesicles , 1989, Nature.

[8]  J. Seagrave,et al.  Mapping gold-labeled receptors on cell surfaces by backscattered electron imaging and digital image analysis: studies of the IgE receptor on mast cells. , 1989, The American journal of anatomy.

[9]  Sitting on the fence , 1989, Nature.

[10]  S. Fleischer,et al.  Isolation and characterization of the inositol trisphosphate receptor from smooth muscle. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[11]  F. Sala,et al.  Calcium diffusion modeling in a spherical neuron. Relevance of buffering properties. , 1990, Biophysical journal.

[12]  J. Meldolesi,et al.  Calreticulin is a candidate for a calsequestrin-like function in Ca2(+)-storage compartments (calciosomes) of liver and brain. , 1990, The Biochemical journal.

[13]  R. Turner,et al.  Propeptide recognition by the vitamin K-dependent carboxylase in early processing of prothrombin and factor X. , 1990, The Biochemical journal.

[14]  E. Bamberg,et al.  Voltage‐dependent pump currents of the sarcoplasmic reticulum Ca2+‐ATPase in planar lipid membranes , 1990, FEBS letters.

[15]  S. Baksh,et al.  Expression of calreticulin in Escherichia coli and identification of its Ca2+ binding domains. , 1991, The Journal of biological chemistry.

[16]  R. Penner,et al.  Depletion of intracellular calcium stores activates a calcium current in mast cells , 1992, Nature.

[17]  J. Keizer,et al.  A single-pool inositol 1,4,5-trisphosphate-receptor-based model for agonist-stimulated oscillations in Ca2+ concentration. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[18]  L. Stryer,et al.  Range of messenger action of calcium ion and inositol 1,4,5-trisphosphate. , 1992, Science.

[19]  J. Putney,et al.  Sustained Ca2+ signaling in mouse lacrimal acinar cells due to photolysis of "caged" glycerophosphoryl-myo-inositol 4,5-bisphosphate. , 1992, The Journal of biological chemistry.

[20]  R. Penner,et al.  A GTP-dependent step in the activation mechanism of capacitative calcium influx. , 1993, The Journal of biological chemistry.

[21]  Eric L. Schwartz,et al.  Computational Neuroscience , 1993, Neuromethods.

[22]  Roger Y. Tsien,et al.  Emptying of intracellular Ca2+ stores releases a novel small messenger that stimulates Ca2+ influx , 1993, Nature.

[23]  I. Bezprozvanny,et al.  Inositol (1,4,5)-trisphosphate (InsP3)-gated Ca channels from cerebellum: conduction properties for divalent cations and regulation by intraluminal calcium , 1994, The Journal of general physiology.

[24]  J. Oliver,et al.  Wortmannin blocks lipid and protein kinase activities associated with PI 3-kinase and inhibits a subset of responses induced by Fc epsilon R1 cross-linking. , 1995, Molecular biology of the cell.

[25]  R. Penner,et al.  Depletion-activated calcium current is inhibited by protein kinase in RBL-2H3 cells. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[26]  J. Keizer,et al.  Effect of Ca2+ influx on intracellular free Ca2+ responses in antigen-stimulated RBL-2H3 cells. , 1996, The American journal of physiology.

[27]  Barry F. Smith,et al.  Domain Decomposition: Parallel Multilevel Methods for Elliptic Partial Differential Equations , 1996 .

[28]  John N. Shadid,et al.  MP Salsa: a finite element computer program for reacting flow problems. Part 1--theoretical development , 1996 .

[29]  J. Johnson,et al.  Effects of Myosin Light Chain Kinase and Peptides on Ca2+ Exchange with the N- and C-terminal Ca2+ Binding Sites of Calmodulin (*) , 1996, The Journal of Biological Chemistry.

[30]  R. Zucker,et al.  Mitochondrial Involvement in Post-Tetanic Potentiation of Synaptic Transmission , 1997, Neuron.

[31]  R. Penner,et al.  The Store-Operated Calcium Current ICRAC: Nonlinear Activation by InsP3 and Dissociation from Calcium Release , 1997, Cell.

[32]  M. Fill,et al.  Identification and Functional Reconstitution of the Type 2 Inositol 1,4,5-Trisphosphate Receptor from Ventricular Cardiac Myocytes* , 1997, The Journal of Biological Chemistry.

[33]  M. Blaustein,et al.  Spatially and Functionally Distinct Ca2+ Stores in Sarcoplasmic and Endoplasmic Reticulum , 1997, Science.

[34]  L. Sklar,et al.  Cooperation between the Fc epsilonR1 and formyl peptide receptor signaling pathways in RBL(FPR) cells: the contribution of receptor-specific Ca2+ mobilization responses. , 1997, Biochemical and biophysical research communications.

[35]  L. Missiaen,et al.  Molecular and Functional Evidence for Multiple Ca2+-binding Domains in the Type 1 Inositol 1,4,5-Trisphosphate Receptor* , 1997, The Journal of Biological Chemistry.

[36]  J. Russell,et al.  Role of sarcoplasmic/endoplasmic-reticulum Ca2+-ATPases in mediating Ca2+ waves and local Ca2+-release microdomains in cultured glia. , 1997, The Biochemical journal.

[37]  John N. Shadid,et al.  Efficient Parallel Computation of Unstructured Finite Element Reacting Flow Solutions , 1997, Parallel Comput..

[38]  A S Verkman,et al.  Monte Carlo analysis of obstructed diffusion in three dimensions: application to molecular diffusion in organelles. , 1998, Biophysical journal.

[39]  C. Taylor,et al.  Luminal Ca2+ regulates passive Ca2+ efflux from the intracellular stores of hepatocytes. , 1998, The Biochemical journal.

[40]  Joel R. Stiles,et al.  Monte Carlo simulation of neuro-transmitter release using MCell, a general simulator of cellular physiological processes , 1998 .

[41]  R. Wojcikiewicz,et al.  Differences among type I, II, and III inositol-1,4,5-trisphosphate receptors in ligand-binding affinity influence the sensitivity of calcium stores to inositol-1,4,5-trisphosphate. , 1998, Molecular pharmacology.

[42]  R. Dolmetsch,et al.  A fluorometric method for estimating the calcium content of internal stores. , 1998, Cell Calcium.

[43]  J. Meldolesi,et al.  The Heterogeneity of ER Ca2+ Stores Has a Key Role in Nonmuscle Cell Signaling and Function , 1998, The Journal of cell biology.

[44]  J. Pfeiffer,et al.  Wortmannin-Sensitive Phosphorylation, Translocation, and Activation of PLCγ1, but Not PLCγ2, in Antigen-stimulated RBL-2H3 Mast Cells , 1998 .

[45]  Alex J. Smith,et al.  Calcium-dependent clustering of inositol 1,4,5-trisphosphate receptors. , 1998, Molecular biology of the cell.

[46]  M Opas,et al.  Calreticulin: one protein, one gene, many functions. , 1999, The Biochemical journal.

[47]  S. A. Barker,et al.  Multiple roles for PI 3‐kinase in the regulation of PLCγ activity and Ca2+ mobilization in antigen‐stimulated mast cells , 1999, Journal of leukocyte biology.

[48]  Erik F. Y. Hom,et al.  Diffusion of green fluorescent protein in the aqueous-phase lumen of endoplasmic reticulum. , 1999, Biophysical journal.

[49]  Ion I. Moraru,et al.  Morphological Control of Inositol-1,4,5-Trisphosphate–Dependent Signals , 1999, The Journal of cell biology.

[50]  John N. Shadid,et al.  MPSalsa Version 1.5: A Finite Element Computer Program for Reacting Flow Problems: Part 1 - Theoretical Development , 1999 .

[51]  M. Berman.  Regulation of Ca2+ transport by sarcoplasmic reticulum Ca2+-ATPase at limiting [Ca2+]. , 1999, Biochimica et biophysica acta.

[52]  D. Bers,et al.  Potentiation of fractional sarcoplasmic reticulum calcium release by total and free intra-sarcoplasmic reticulum calcium concentration. , 2000, Biophysical journal.

[53]  A. M. Riley,et al.  InsP4 facilitates store-operated calcium influx by inhibition of InsP3 5-phosphatase , 2000, Nature.

[54]  P. M. Hinkle,et al.  Rapid Turnover of Calcium in the Endoplasmic Reticulum during Signaling , 2000, The Journal of Biological Chemistry.

[55]  Alexander J. Smith,et al.  p110β and p110δ Phosphatidylinositol 3-Kinases Up-regulate FcεRI-activated Ca2+ Influx by Enhancing Inositol 1,4,5-Trisphosphate Production* , 2001, The Journal of Biological Chemistry.

[56]  M. Tomita.  Whole-cell simulation: a grand challenge of the 21st century. , 2001, Trends in biotechnology.

[57]  K W Young,et al.  Calcium puffs are generic InsP(3)-activated elementary calcium signals and are downregulated by prolonged hormonal stimulation to inhibit cellular calcium responses. , 2001, Journal of cell science.

[58]  Fred J Sigworth,et al.  Three‐dimensional structure of the type 1 inositol 1,4,5‐trisphosphate receptor at 24 Å resolution , 2002, The EMBO journal.

[59]  P. Jung,et al.  Stochastic properties of Ca(2+) release of inositol 1,4,5-trisphosphate receptor clusters. , 2002, Biophysical journal.

[60]  L. Margolin,et al.  On balanced approximations for time integration of multiple time scale systems , 2003 .

[61]  M. Opas,et al.  Is all of the endoplasmic reticulum created equal? The effects of the heterogeneous distribution of endoplasmic reticulum Ca2+-handling proteins , 2003, The Journal of cell biology.

[62]  T. Smani,et al.  Ca2+-independent Phospholipase A2 Is a Novel Determinant of Store-operated Ca2+ Entry* , 2003, The Journal of Biological Chemistry.

[63]  L. Loew,et al.  Quantitative cell biology with the Virtual Cell. , 2003, Trends in cell biology.

[64]  S. Morris,et al.  Domain organization of the type 1 inositol 1,4,5-trisphosphate receptor as revealed by single-particle analysis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[65]  V. Bolotina.  Store-Operated Channels: Diversity and Activation Mechanisms , 2004, Science's STKE.

[66]  J. Shadid,et al.  Studies on the accuracy of time-integration methods for the radiation-diffusion equations , 2004 .

[67]  M. Falcke,et al.  Release currents of IP(3) receptor channel clusters and concentration profiles. , 2004, Biophysical journal.

[68]  S. Snyder,et al.  Inositol 1,4,5-trisphosphate receptors as signal integrators. , 2004, Annual review of biochemistry.

[69]  D. T. Yue,et al.  Functional Stoichiometry and Local Enrichment of Calmodulin Interacting with Ca2+ Channels , 2004, Science.

[70]  I. Bezprozvanny.  The inositol 1,4,5-trisphosphate receptors. , 2005, Cell calcium.

[71]  J. Sneyd,et al.  Models of the inositol trisphosphate receptor. , 2005, Progress in biophysics and molecular biology.

[72]  I. Bezprozvanny,et al.  Modulation of mammalian inositol 1,4,5-trisphosphate receptor isoforms by calcium: a role of calcium sensor region. , 2005, Biophysical journal.

[73]  Maryann E Martone,et al.  Evidence for Ectopic Neurotransmission at a Neuronal Synapse , 2005, Science.

[74]  Irina Baran,et al.  Gating mechanisms of the type-1 inositol trisphosphate receptor. , 2005, Biophysical journal.

[75]  I. Bezprozvanny,et al.  Functional characterization of mammalian inositol 1,4,5-trisphosphate receptor isoforms. , 2005, Biophysical journal.

[76]  B. Hendrickson.  The Chaco User � s Guide Version , 2005 .

[77]  J. Shadid,et al.  Studies of the Accuracy of Time Integration Methods for Reaction-Diffusion Equations ∗ , 2005 .

[78]  Takafumi Inoue,et al.  Cluster Formation of Inositol 1,4,5-Trisphosphate Receptor Requires Its Transition to Open State* , 2005, Journal of Biological Chemistry.