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Duan, Jingxian Navarro Dorado, Jorge Clark, Jill Kinnear, Nicholas Meinke, Peter Schirmer, Eric Evans, Anthony Mark 2025-01-22T16:38:15Z 2025-01-22T16:38:15Z 2019 Duan, J., Navarro-Dorado, J., Clark, J.H. et al. The cell-wide web coordinates cellular processes by directing site-specific Ca2+ flux across cytoplasmic nanocourses. Nat Commun 10, 2299 (2019). https://doi.org/10.1038/s41467-019-10055-w 10.1038/S41467-019-10055-W https://hdl.handle.net/20.500.14352/115653 2041-1723 https://doi.org/10.1038/S41467-019-10055-W Ca2+ coordinates diverse cellular processes, yet how function-specific signals arise is enigmatic. We describe a cell-wide network of distinct cytoplasmic nanocourses with the nucleus at its centre, demarcated by sarcoplasmic reticulum (SR) junctions (≤400 nm across) that restrict Ca2+ diffusion and by nanocourse-specific Ca2+-pumps that facilitate signal segregation. Ryanodine receptor subtype 1 (RyR1) supports relaxation of arterial myocytes by unloading Ca2+ into peripheral nanocourses delimited by plasmalemma-SR junctions, fed by sarco/endoplasmic reticulum Ca2+ ATPase 2b (SERCA2b). Conversely, stimulus-specified increases in Ca2+ flux through RyR2/3 clusters selects for rapid propagation of Ca2+ signals throughout deeper extraperinuclear nanocourses and thus myocyte contraction. Nuclear envelope invaginations incorporating SERCA1 in their outer nuclear membranes demarcate further diverse networks of cytoplasmic nanocourses that receive Ca2+ signals through discrete RyR1 clusters, impacting gene expression through epigenetic marks segregated by their associated invaginations. Critically, this circuit is not hardwired and remodels for different outputs during cell proliferation. eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 International The cell-wide web coordinates cellular processes by directing site-specific Ca2+ flux across cytoplasmic nanocourses journal article