Ca2+ signalling system initiated by endoplasmic reticulum stress stimulates PERK activation

Abstract

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. 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.

Keywords: (PKR)-like-ER kinase (PERK); Calcium signalling; Inositol triphosphate receptor; Translocon; Unfolded protein response.