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

Constanza Feliziani, Macarena Fernandez, Gonzalo Quassollo, Deborah Holstein, Sebastián M. Bairo, James C. Paton, Adrienne W. Paton, Juan de Batista, James D. Lechleiter, Mariana Bollo

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number102622
JournalCell Calcium
Volume106
DOIs
StatePublished - Sep 2022

Keywords

  • (PKR)-like-ER kinase (PERK)
  • Calcium signalling
  • Inositol triphosphate receptor
  • Translocon
  • Unfolded protein response

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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