Endoplasmic reticulum stress induces a novel Ca2+ signalling system initiated by Ca2+ microdomains

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 homeostasis cannot be restored, UPR signalling ultimately induces apoptosis. Ca2+ depletion in the ER is a potent inducer of ER stress. Despite the ubiquity of Ca2+ as intracellular messenger, the precise mechanism (s) by which Ca2+ release affects the UPR remains unknown. Use of a genetically encoded Ca2+ indicator (GCamP6) that is tethered to the ER membrane, uncovered novel Ca2+ signalling events initiated by Ca2+ microdomains in human astrocytes under ER stress, as well as in a cell model deficient in all three IP3 Receptor isoforms. Pharmacological and molecular studies indicate that these local events are mediated by translocons. Together, these data reveal the existence of a previously unrecognized mechanism by which stressor-mediated Ca2+ release regulates ER stress.