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The 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 homeostasis. If this cannot be done, UPR signalling ultimately induces apoptosis. Ca(2+) depletion in the ER is a potent inducer of ER stress. Despite the ubiquity of Ca(2+) as an intracellular messenger, the precise mechanism(s) by which Ca(2+) release affects the UPR remains unknown. Tethering a genetically encoded Ca(2+) indicator (GCamP6) to the ER membrane revealed novel Ca(2+) signalling events initiated by Ca(2+) 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 Ca(2+) microdomains impact (PKR)-like-ER kinase (PERK), an UPR sensor, activation. These findings reveal the existence of a Ca(2+) signal mechanism by which stressor-mediated Ca(2+) release regulates ER stress. |
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