Duan, JingxianNavarro Dorado, JorgeClark, JillKinnear, NicholasMeinke, PeterSchirmer, EricEvans, Anthony Mark2025-01-222025-01-222019Duan, 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-w10.1038/S41467-019-10055-Whttps://hdl.handle.net/20.500.14352/115653Ca2+ 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.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/journal article2041-1723https://doi.org/10.1038/S41467-019-10055-Wopen access61Ciencias Biomédicas24 Ciencias de la Vida