Ca signalling system initiated by endoplasmic reticulum stress stimulates PERK activation.

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