Feliziani, C.Fernandez, M.Quassollo, G.Holstein, D.Bairo, S.M.Paton, J.C.Paton, A.W.de Batista, J.Lechleiter, J.D.Bollo, M.2025-08-052025-08-052022Cell Calcium, 2022; 106:102622-1-102622-160143-41601532-1991https://hdl.handle.net/2440/146538The accumulation of unfolded proteins within the Endoplasmic Reticulum (ER) activates a signal transduction pathway termed the unfolded protein response (UPR), which attempts to restore ER homoeostasis. If this cannot be done, UPR signalling ultimately induces apoptosis. Ca²⁺ depletion in the ER is a potent inducer of ER stress. Despite the ubiquity of Ca²⁺ as an intracellular messenger, the precise mechanism(s) by which Ca²⁺ release affects the UPR remains unknown. Tethering a genetically encoded Ca²⁺ indicator (GCamP6) to the ER membrane revealed novel Ca²⁺ signalling events initiated by Ca²⁺ microdomains in human astrocytes under ER stress, induced by tunicamycin (Tm), an N-glycosylation inhibitor, as well as in a cell model deficient in all three inositol triphosphate receptor isoforms. Pharmacological and molecular studies indicate that these local events are mediated by translocons and that the Ca²⁺ microdomains impact (PKR)-like-ER kinase (PERK), an UPR sensor, activation. These findings reveal the existence of a Ca²⁺ signal mechanism by which stressor-mediated Ca²⁺ release regulates ER stress.en© 2022 Elsevier Ltd. All rights reserved.Unfolded protein response; Calcium signalling; Translocon; Inositol triphosphate receptor; (PKR)-like-ER kinase (PERK)Endoplasmic ReticulumHumanseIF-2 KinaseSignal TransductionApoptosisUnfolded Protein ResponseEndoplasmic Reticulum StressJournal article10.1016/j.ceca.2022.102622618975Paton, J.C. [0000-0001-9807-5278]