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Endoplasmic Reticulum Geometry Dictates Neuronal Bursting via Calcium Store Refill Rates and Exposes Selective Neuronal Vulnerability.

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  1. [1] § Modelling › Mathematical Model for Ca2+ Oscillations ↔ model_run.m, lines 6 to 53 · score 0.76 · simplified model, SERCA pumping, ER lumen, clearance, IP3, activation · Report a mismatch
  2. [2] § Modelling › Model Parameters ↔ model_run.m, lines 6 to 53 · score 0.76 · half max, IP3R, strength, binding, cytoplasmic, WT · Report a mismatch
  3. [3] § Modelling › Mathematical Model for Ca2+ Oscillations ↔ calcium_ode_cyto_V.m, the whole file · a weak match · score 0.56 · SERCA pumping, IP3 receptors, SOCE, dynamics · Report a mismatch

Paper

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The authors' code

MATLAB · 85 lines · 2.6 KB · no license · 2 matches

  1. % This script simulates Ca2+ dynamics with hardcoded parameters for two cases:
  2. % - Wild Type (WT): set volchange = 1 and params.k_soce = 6.5227
  3. % - RTN3OE: set volchange = 4.3808 and params.k_soce = 3.9583
  4. % Ensure the matching k_soce value is uncommented when switching between cases
  5. %% Setup Ca2+ model parameters
  6. volchange = 1; % Set to 1 to run simulation with the ER volume of WT
  7. % Volume of ER and cytosol (μm^3)
  8. params.VER = 212;
  9. params.Vcyto = 4/3 * pi * (10^3 - 5^3) - params.VER; % Cell minus nucleus minus ER
  10. % IP3R Ca2+ release rate (μm^3/s)
  11. params.v1 = 69.075;
  12. % Passive leak rate (μm^3/s)
  13. params.v2 = 0.00;
  14. % SERCA pump rate (μM·μm^3/s)
  15. params.v3 = 496;
  16. % Cytoplasmic clearance rate (μM·μm^3/s)
  17. params.v4 = 368;
  18. % Half-max [Ca2+] for cytosolic clearance (μM)
  19. params.k_pl = 0.106;
  20. % SOCE entry rate (μm^3/s)
  21. params.k_soce = 6.5227; % for WT
  22. %params.k_soce = 3.9583; % for RTN3OE
  23. % Extracellular Ca2+ concentration (μM)
  24. params.c_cs = 200;
  25. % Half-max constants for IP3R gating (μM)
  26. params.k_er = 0.117; % SERCA half-max [Ca2+] (μM)
  27. params.d_ip3 = 0.1300; % IP3 binding (μM)
  28. params.d_act = 0.0823; % Activation by Ca2+ (μM)
  29. % inhibition by Ca, not using the simplified model, different IP3 binding
  30. % strength depending on whether Ca is present in other sites
  31. d2 = 1.049; d3 = 0.9434;
  32. params.d_inh = d2*(params.IP3 + params.d_ip3)/(params.IP3 + d3); % μM
  33. params.a = 0.5940; % h-gate kinetics (1/μM/s)
  34. % IP3 concentration (μM)
  35. params.IP3 = 0.4;
  36. % Buffer parameters in ER lumen
  37. params.k_D = 201.6; % Dissociation constant (μM)
  38. params.S = 2700 / volchange; % Total buffer site conc. (μM)
  39. params0 = params; % Save a copy
  40. %% Initial conditions
  41. c_cyto0 = 0.06; % Initial cytosolic free Ca2+ (μM)
  42. h0 = 0.8; % Initial h-inactivation variable
  43. u_er0 = 170; % Initial ER free Ca2+ (μM)
  44. c_er0 = u_er0 + u_er0 * params.S / (u_er0 + params.k_D); % Total ER Ca2+ (free + bound)
  45. % Initial state vector: [cytosol Ca2+, h, ER free Ca2+, ER total Ca2+]
  46. y0 = [c_cyto0; h0; u_er0; c_er0];
  47. % Time span (s)
  48. tspan = [0, 480];
  49. % Solve ODE system
  50. [t, y] = ode45(@(t, y) calcium_ode_cyto_V(t, y, params), tspan, y0);
  51. %% Plot cytosolic and ER free Ca2+ over time
  52. subplot(2,1,1);
  53. plot(t/60, y(:,1), 'LineWidth', 2);
  54. plot_cleanup(gca, 'FontSize', 16)
  55. ylabel('$c_\mathrm{cyto}\;\; \mu M$');
  56. xlabel('Time (min)');
  57. title('Cytosol Ca$^{2+}$');
  58. legend off
  59. subplot(2,1,2);
  60. plot(t/60, y(:,3), 'LineWidth', 2);
  61. plot_cleanup(gca, 'FontSize', 16)
  62. ylabel('$u_\mathrm{ER}\;\; \mu M$');
  63. xlabel('Time (min)');
  64. title('ER free Ca$^{2+}$');
  65. legend off

model_run.m at commit f577f4e, no license · at the source

Overview

Authors: Valentina Davi1, Pierre Parutto1, Yuyi Zhang2, Tasuku Konno1, Cecile Crapart1, Raquel Pereira3,4, John P. Franklin5,6, Mosab Ali Awadelkareem7, Daniel C Maddison1, Michael J. Devine5,8, Edgar R. Gomes3,4, Joseph Chambers9, Elena Koslover2, Edward Avezov1
  1. Department of Clinical Neurosciences UK Dementia Research Institute at University of Cambridge Cambridge UK
  2. Department of Physics University of California San Diego, La Jolla California USA
  3. GIMM – Gulbenkian Institute for Molecular Medicine Avenida Prof. Egas Moniz Lisboa Portugal
  4. Faculdade de Medicina Universidade De Lisboa Av. Prof. Egas Moniz Lisboa Portugal
  5. Mitochondrial Neurobiology Laboratory The Francis Crick Institute London UK
  6. Department of Basic and Clinical Neuroscience Institute of Psychiatry Psychology and Neuroscience King's College London London UK
  7. Nuffield Department of Clinical Neurosciences University of Oxford Oxford UK
  8. Department of Clinical and Movement Neurosciences UCL Queen Square Institute of Neurology University College London London UK
  9. Cambridge Institute for Medical Research (CIMR) Department of Medicine University of Cambridge Cambridge UK
Institutions: University of Cambridge (United Kingdom); UK Dementia Research Institute (United Kingdom); University of California San Diego (United States); University of Lisbon (Portugal); Gulbenkian Institute for Molecular Medicine (Portugal); King's College London (United Kingdom); The Francis Crick Institute (United Kingdom); University of Oxford (United Kingdom); UCL Queen Square Institute of Neurology (United Kingdom); University College London (United Kingdom)
Journal: Advanced science (Weinheim, Baden-Wurttemberg, Germany), volume 13, issue 36, article e21101
Dates: received 27 October 2025; accepted 13 March 2026; published online 31 March 2026; in print June 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1002/advs.202521101 · PMID 41915835 · PMCID PMC13317608 · OpenAlex W7147087334
Open access: gold, a free copy (OpenAlex)
Status: code verified (how the code is found and verified)
Categories: human (organism), cellular / molecular (subfield)
Methods: Statistics, fMRI & imaging, Smoothing, state filtering, decompositions
Keywords: calcium oscillations, endoplasmic reticulum Ca2+ refill, endoplasmic reticulum morphology, human iPSC‐derived neurons, modelling, neurodegenerative diseases, neuronal firing
MeSH: Calcium*, Calcium Signaling*, Endoplasmic Reticulum*, Induced Pluripotent Stem Cells*, Neurons*, Humans (* major topic)
Topic: Cellular transport and secretion (Cell Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: UK Dementia Research Institute (UKDRI‐2203); Medical Research Council; National Science Foundation (2034482); Alzheimer Society of Canada (grant AS‐525 (AS‐PhD 19a‐015)); Evelyn Trust
Citations: cited by 1 paper (Europe PMC); 69 references in the paper
Research resources: HEK293T RRID:CVCL_0063, COS‐7 RRID:CVCL_0224, Human: NGN2 iPSCs RRID:CVCL_C7XJ, Fiji (ImageJ v2) RRID:SCR_002285, Leica Application Suite X RRID:SCR_013673, IncuCyte S3 Live Cell Analysis System RRID:SCR_023147

Abstract

The endoplasmic reticulum (ER)’s continuous morphology is tightly controlled by ER‐shaping proteins, whose genetic or expression defects drive a spectrum of neurodegenerative disorders from Hereditary Spastic Paraplegia to Alzheimer's disease. Why perturbations in ER morphology manifest specifically in neurons remains unknown. Here, by coupling visualisation of global sub‐Hz firing bursts to ER ultrastructural manipulations in human inducible Pluripotent Stem Cells (hiPSC)‐derived cortical neurons, alongside physical simulations, we establish a key ER structure‐function principle: neuronal ER architecture dictates Ca2+ replenishment speed. Altering ER structure hinders network ER luminal connectivity and Ca2+ propagation from refill points at plasma membrane contact sites, impairing the ER's capability to supply repetitive Ca2+ bursts. The ER morpho‐regulatory control of Ca2+ refill speed thus constitutes a switch on neuronal activity. Further, perturbed ER shape also abolishes Ca2+ firing and contraction in primary skeletal muscle cells. These results expose the selective vulnerability of Ca2+‐firing cells to ER structural disruptions, rationalizing ER dysfunction in neurodegeneration and unveiling a new role for the continuous ER morphology that could apply universally to Ca2+‐firing cells.

Reproduced under the paper's license (CC BY), from the paper cited above.

Repositories

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lenafabr/networkSpreadFVM

License: GPL-3.0
State: the link answers, verified on 31 October 2026
Evidence: files inventoried
Commit: 7a33595ded23d64e9ec2ef41c439528dae422c98, 22 January 2026
Languages: MATLAB (27), Fortran (20)
Size: 80 files, 47 scripts
Software Heritage: not archived
Found in: the text, “Simulations of Network Ca 2+ Refill”
Holds: README, license file, documentation
Not found: CITATION.cff, environment file, tests, continuous integration
Availability: 2 checks, the latest on 31 October 2026: the link answers
  • 31 October 2026: the link answers
  • 30 September 2026: the link answers
49 files

lenafabr/aspatialCaERrefill

License: none: the authors keep all their rights
State: the link answers, verified on 31 October 2026
Evidence: files inventoried
Commit: f577f4e0f280742c4c111cffdb0f76c622e352bc, 11 July 2025
Languages: MATLAB (2)
Size: 3 files, 2 scripts
Software Heritage: not archived
Found in: the text, “Implementation”
Holds: README
Not found: license file, CITATION.cff, environment file, tests, continuous integration, documentation
Availability: 2 checks, the latest on 31 October 2026: the link answers
  • 31 October 2026: the link answers
  • 30 September 2026: the link answers
3 files

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Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 14 authors, 7 keywords, 6 MeSH terms, 5 funders, 68 references, 6 RRIDs.

Cite

This paper

Davi, V., Parutto, P., Zhang, Y., Konno, T., Crapart, C., Pereira, R., Franklin, J. P., Awadelkareem, M. A., Maddison, D. C., Devine, M. J., Gomes, E. R., Chambers, J., Koslover, E., & Avezov, E. (2026). Endoplasmic Reticulum Geometry Dictates Neuronal Bursting via Calcium Store Refill Rates and Exposes Selective Neuronal Vulnerability. Advanced science (Weinheim, Baden-Wurttemberg, Germany), 13(36), e21101. https://doi.org/10.1002/advs.202521101

BibTeX

@article{davi2026endoplasmic,
author = {Davi, Valentina and Parutto, Pierre and Zhang, Yuyi and Konno, Tasuku and Crapart, Cecile and Pereira, Raquel and Franklin, John P. and Awadelkareem, Mosab Ali and Maddison, Daniel C and Devine, Michael J. and Gomes, Edgar R. and Chambers, Joseph and Koslover, Elena and Avezov, Edward},
title = {{Endoplasmic Reticulum Geometry Dictates Neuronal Bursting via Calcium Store Refill Rates and Exposes Selective Neuronal Vulnerability}},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
year = {2026},
month = mar,
volume = {13},
number = {36},
pages = {e21101},
publisher = {Wiley},
issn = {2198-3844},
doi = {10.1002/advs.202521101},
url = {https://doi.org/10.1002/advs.202521101},
pmid = {41915835},
pmcid = {PMC13317608}
}

RIS

TY - JOUR
AU - Davi, Valentina
AU - Parutto, Pierre
AU - Zhang, Yuyi
AU - Konno, Tasuku
AU - Crapart, Cecile
AU - Pereira, Raquel
AU - Franklin, John P.
AU - Awadelkareem, Mosab Ali
AU - Maddison, Daniel C
AU - Devine, Michael J.
AU - Gomes, Edgar R.
AU - Chambers, Joseph
AU - Koslover, Elena
AU - Avezov, Edward
TI - Endoplasmic Reticulum Geometry Dictates Neuronal Bursting via Calcium Store Refill Rates and Exposes Selective Neuronal Vulnerability
T2 - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
J2 - Adv Sci (Weinh)
PY - 2026
DA - 2026/03/31
VL - 13
IS - 36
SP - e21101
SN - 2198-3844
PB - Wiley
DO - 10.1002/advs.202521101
UR - https://doi.org/10.1002/advs.202521101
LA - en
ER -

CSL-JSON

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"id": "10.1002/advs.202521101",
"type": "article-journal",
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"container-title": "Advanced science (Weinheim, Baden-Wurttemberg, Germany)",
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{
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"PMID": "41915835",
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31
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}

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